ClinVar Miner

Submissions for variant NM_000135.4(FANCA):c.3349-3C>T

gnomAD frequency: 0.00006  dbSNP: rs373861415
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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Counsyl RCV000665511 SCV000789649 uncertain significance Fanconi anemia complementation group A 2017-02-08 criteria provided, single submitter clinical testing
Illumina Laboratory Services, Illumina RCV000665511 SCV001276815 uncertain significance Fanconi anemia complementation group A 2018-01-12 criteria provided, single submitter clinical testing This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
Invitae RCV001242629 SCV001415730 uncertain significance Fanconi anemia 2022-06-13 criteria provided, single submitter clinical testing This sequence change falls in intron 33 of the FANCA gene. It does not directly change the encoded amino acid sequence of the FANCA protein. It affects a nucleotide within the consensus splice site. This variant is present in population databases (rs373861415, gnomAD 0.02%). This variant has been observed in individual(s) with clinical features of Shwachman-Diamond syndrome (PMID: 26492932). ClinVar contains an entry for this variant (Variation ID: 550696). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Sema4, Sema4 RCV001242629 SCV002534999 uncertain significance Fanconi anemia 2021-11-04 criteria provided, single submitter curation
Preventiongenetics, part of Exact Sciences RCV003432720 SCV004118432 uncertain significance FANCA-related condition 2023-01-19 criteria provided, single submitter clinical testing The FANCA c.3349-3C>T variant is predicted to interfere with splicing. This variant is predicted to have a minor impact on splicing at the consensus splice site based on splicing prediction programs. However, these prediction programs are not equivalent to functional evidence. This variant was reported in the compound heterozygous state with a second FANCA variant (c.1340C>T, p.Ser447Leu) in an individual with myelodysplastic syndrome / acute myeloid leukemia; however, this individual also had two compound heterozygous variants in the SBDS gene (Churpek et al. 2015. PubMed ID: 26492932). This variant is reported in 0.015% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/16-89813301-G-A) and has been interpreted in ClinVar as uncertain (https://preview.ncbi.nlm.nih.gov/clinvar/variation/550696/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.
Natera, Inc. RCV001242629 SCV002092536 uncertain significance Fanconi anemia 2020-01-31 no assertion criteria provided clinical testing

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