ClinVar Miner

Submissions for variant NM_144670.6(A2ML1):c.3789C>G (p.Asn1263Lys)

gnomAD frequency: 0.00327  dbSNP: rs144876785
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000858726 SCV000556902 benign not provided 2024-01-22 criteria provided, single submitter clinical testing
GeneDx RCV000858726 SCV000721698 benign not provided 2020-05-04 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000474241 SCV001338304 benign not specified 2020-02-14 criteria provided, single submitter clinical testing Variant summary: A2ML1 c.3789C>G (p.Asn1263Lys) 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 0.0011 in 280962 control chromosomes, predominantly at a frequency of 0.012 within the African or African-American subpopulation in the gnomAD database, including 1 homozygotes. The observed variant frequency within African or African-American control individuals in the gnomAD database is approximately 3000 fold of the estimated maximal expected allele frequency for a pathogenic variant in A2ML1 causing Noonan Syndrome phenotype (4e-06), strongly suggesting that the variant is a benign polymorphism found primarily in populations of African or African-American origin. To our knowledge, no experimental evidence demonstrating its impact on protein function have been reported. Two ClinVar submitters (evaluation after 2014) cite the variant as benign/likely benign. Based on the evidence outlined above, the variant was classified as benign.

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