ClinVar Miner

Submissions for variant NM_000135.4(FANCA):c.4036G>A (p.Ala1346Thr)

gnomAD frequency: 0.00056  dbSNP: rs17227396
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Total submissions: 12
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Illumina Laboratory Services, Illumina RCV001094347 SCV000399810 likely benign Fanconi anemia complementation group A 2017-04-27 criteria provided, single submitter clinical testing This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign.
Labcorp Genetics (formerly Invitae), Labcorp RCV000356305 SCV000558861 benign Fanconi anemia 2024-01-31 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000120954 SCV002103352 benign not specified 2023-12-07 criteria provided, single submitter clinical testing Variant summary: FANCA c.4036G>A (p.Ala1346Thr) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.0023 in 1607150 control chromosomes, predominantly at a frequency of 0.037 within the South Asian subpopulation in the gnomAD database (v4.0 dataset), including 104 homozygotes. The observed variant frequency within South Asian control individuals in the gnomAD database is approximately 17-fold of the estimated maximal expected allele frequency for a pathogenic variant in FANCA causing Fanconi Anemia phenotype (0.0022), strongly suggesting that the variant is a benign polymorphism found primarily in populations of South Asian origin. Although reported in the literature, to our knowledge, no compelling evidence supporting a pathogenic outcome has been ascertained for c.4036G>A in individuals affected with Fanconi Anemia, and no experimental evidence demonstrating its impact on protein function have been reported. Ten other submitters have cited clinical-significance assessments for this variant to ClinVar after 2014, and all classified this variant as Benign/Likely Benign. Based on the evidence outlined above, the variant was classified as benign.
Sema4, Sema4 RCV000356305 SCV002535038 benign Fanconi anemia 2020-12-21 criteria provided, single submitter curation
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000120954 SCV002774401 benign not specified 2021-06-13 criteria provided, single submitter clinical testing
CeGaT Center for Human Genetics Tuebingen RCV001357339 SCV004143589 benign not provided 2023-06-01 criteria provided, single submitter clinical testing FANCA: BP4, BS1, BS2
ITMI RCV000120954 SCV000085122 not provided not specified 2013-09-19 no assertion provided reference population
Leiden Open Variation Database RCV001094347 SCV001425730 pathogenic Fanconi anemia complementation group A 2020-02-28 flagged submission curation Curator: Arleen D. Auerbach. Submitter to LOVD: Johan de Winter.
Natera, Inc. RCV001094347 SCV001458743 benign Fanconi anemia complementation group A 2020-09-16 no assertion criteria provided clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System RCV001357339 SCV001552785 likely benign not provided no assertion criteria provided clinical testing The FANCA p.Ala1346Thr variant was identified in probands affected by Fanconi Anemia. The variant was identified in 2 out of 122 proband chromosomes (frequency = 0.016) among Indian patients affected by Fanconi Anemia (Solanki_2016_PMID: 26799702). The variant was also identified in 1 out of 80 proband chromosomes (frequency = 0.006) in a compound heterozygous state among patients affected by Fanconi Anemia whose ethnicity was not specified (Ameziane_2008_PMID: 17924555). The variant was also identified in the Geno2MP database, found in a heterozygous state in 18 affected individuals and in a homozygous state in 1 affected individual. The variant was also identified in a heterozygous state in 4 relatives of affected individuals. The p.Ala1346Thr variant was identified in dbSNP (ID: rs17227396) as “With other allele.” The p.Ala1346Thr variant was identified in ClinVar, and was classified as likely benign by Illumina in 2016 and as benign by Invitae in 2017. The variant was found in the ClinVitae (reported as “Conflicting Interpretations of Pathogenicity”) and LOVD 3.0 (reported as “Affects function”) databases. The variant was not identified in COGR, Cosmic, or MutDB databases. The p.Ala1346Thr variant was identified in control databases in 1215 of 282704 chromosomes (32 homozygous) at a frequency of 0.004298 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: South Asian in 1150 of 30614 chromosomes (freq: 0.03756), Other in 18 of 7224 chromosomes (freq: 0.002492), African in 35 of 24956 chromosomes (freq: 0.001402), Latino in 5 of 35428 chromosomes (freq: 0.000141), East Asian in 2 of 19946 chromosomes (freq: 0.0001), European (non-Finnish) in 5 of 129056 chromosomes (freq: 0.000039), while the variant was not observed in the Ashkenazi Jewish, and European (Finnish) populations. The p.Ala1346 residue is not conserved in mammals and four out of fivecomputational analyses (SIFT, AlignGVGD, BLOSUM, and MutationTaster) do not suggest a high likelihood of impact to the protein. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, and GeneSplicer) do not predict a difference in splicing. In summary, based on the above information this variant meets our laboratory's criteria to be classified as likely benign. References: Solanki A, Mohanty P, Shukla P, Rao A, Ghosh K, Vundinti BR. FANCA Gene Mutations with 8 Novel Molecular Changes in Indian Fanconi Anemia Patients. PLoS One. 2016 Jan 22;11(1):e0147016. doi: 10.1371/journal.pone.0147016. eCollection 2016. PubMed PMID: 26799702; PubMed Central PMCID: PMC4723128 Ameziane N, Errami A, Léveillé F, Fontaine C, de Vries Y, van Spaendonk RM, de Winter JP, Pals G, Joenje H. Genetic subtyping of Fanconi anemia by comprehensive mutation screening. Hum Mutat. 2008 Jan;29(1):159-66. PubMed PMID: 17924555. Geno2MP, NHGRI/NHLBI University of Washington-Center for Mendelian Genomics (UW-CMG), Seattle, WA (URL: http://geno2mp.gs.washington.edu [Accessed November 28, 2018].
Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC) RCV001357339 SCV001800621 likely benign not provided no assertion criteria provided clinical testing
Genome Diagnostics Laboratory, Amsterdam University Medical Center RCV000120954 SCV001807727 benign not specified no assertion criteria provided clinical testing

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