ClinVar Miner

Submissions for variant NM_001354689.3(RAF1):c.1728+4A>G (rs771344560)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ClinGen RASopathy Variant Curation Expert Panel RCV000467009 SCV000616481 benign Rasopathy 2017-04-18 reviewed by expert panel curation The filtering allele frequency of the c.1668+4A>G variant in the RAF1 gene is 0.053% (11/11576) of Latino chromosomes by the Exome Aggregation Consortium, which is a high enough frequency to be classified as benign based on thresholds defined by the ClinGen RASopathy Expert Panel (BA1; PMID:29493581)
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics RCV000680315 SCV000338455 uncertain significance not provided 2016-01-04 criteria provided, single submitter clinical testing
GeneDx RCV000680315 SCV000515497 likely benign not provided 2017-11-27 criteria provided, single submitter clinical testing This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.
Invitae RCV000467009 SCV000552091 likely benign Rasopathy 2019-12-31 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV001192470 SCV001360609 benign not specified 2019-02-11 criteria provided, single submitter clinical testing Variant summary: RAF1 c.1668+4A>G alters a non-conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. Several computational tools predict an impact on normal splicing: Five predict the no significant impact on splicing. Four predict the variant strengthens a cryptic intronic 5' donor site. However, these predictions have yet to be confirmed by functional studies The variant allele was found at a frequency of 0.00013 in 276966 control chromosomes (gnomAD), reported exclusively within the Latino subpopulation at a frequency of 0.0011 in the gnomAD database. The observed variant frequency within Latino control individuals in the gnomAD database is approximately 44 fold of the estimated maximal expected allele frequency for a pathogenic variant in RAF1 causing Noonan Syndrome and Related Conditions phenotype (2.5e-05), strongly suggesting that the variant is a benign polymorphism found primarily in populations of Latino origin. To our knowledge, no occurrence of c.1668+4A>G in individuals affected with Noonan Syndrome and Related Conditions and no experimental evidence demonstrating its impact on protein function have been reported. Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Multiple laboratories reported the variant with conflicting assessments (2 calling it VUS, and one classifying it as likely benign, and the ClinGen expert panel has classified it as Benign). Based on the evidence outlined above, the variant was classified as benign.

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