Submissions for variant NM_020937.4(FANCM):c.2458A>G (p.Asn820Asp)

gnomAD frequency: 0.00001  dbSNP: rs765507230

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000820042	SCV000960734	uncertain significance	Fanconi anemia	2021-09-01	criteria provided, single submitter	clinical testing	This sequence change replaces asparagine with aspartic acid at codon 820 of the FANCM protein (p.Asn820Asp). The asparagine residue is weakly conserved and there is a small physicochemical difference between asparagine and aspartic acid. This variant is present in population databases (rs765507230, ExAC 0.002%). This variant has not been reported in the literature in individuals affected with FANCM-related conditions. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. 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.
Fulgent Genetics, Fulgent Genetics	RCV002495169	SCV002791753	uncertain significance	Spermatogenic failure 28; Premature ovarian failure 15	2022-05-10	criteria provided, single submitter	clinical testing
GeneDx	RCV001357735	SCV004169706	uncertain significance	not provided	2023-04-04	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001357735	SCV001553291	uncertain significance	not provided		no assertion criteria provided	clinical testing	The FANCM p.Asn794Asp variant was not identified in the literature nor was it identified in ClinVar, Clinvitae, the 1000 Genomes Project, or the NHLBI GO Exome Sequencing Project. The variant was identified in dbSNP (ID: rs765507230) as "NA" and in the Genome Aggregation (Feb 27, 2017) control database in 5 of 250190 chromosomes (1 homozygous) at a frequency of 0.00002. It was observed in the European (Non-Finnish) population in 5 of 113246 chromosomes (freq: 0.000044); it was not observed in the African, Latino, Ashkenazi Jewish, East Asian, European (Finnish), Other, and South Asian populations. The c.2380A>G variant occurs outside of the splicing consensus sequence, however one of four in silico or computational prediction software programs (MaxEntScan) predicts a greater than 10% difference in splicing one basepair upstream of the variant. The p.Asn794 residue is not conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, and MutationTaster) do not suggest a high likelihood of impact to the protein. However, this information is not predictive enough to rule out pathogenicity. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance.