ClinVar Miner

Submissions for variant NM_001354689.3(RAF1):c.1168+9_1168+21del (rs727504451)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ClinGen RASopathy Variant Curation Expert Panel RCV000159065 SCV000616427 benign Rasopathy 2017-04-03 reviewed by expert panel curation The c.1108+9_1108+21del variant in the RAF1 gene has been identified in a patient with an alternate molecular basis for disease (BP5; GeneDx, Partners LMM internal data; GTR Lab ID's: 26957, 21766; ClinVar SCV000205113.4, SCV000209007.2). This variant is a synonymous (silent) variant at a nucleotide that is not highly conserved and is not predicted to impact splicing (BP7). The filtering allele frequency of the c.1108+9_1108+21del variant in the RAF1 gene is 0.0637% (54/66698) for European (Non-Finnish) 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 for autosomal dominant RASopathy variants (BA1). In summary, this variant meets criteria to be classified as benign. RASopathy-specific ACMG/AMP criteria applied (PMID:29493581): BA1, BP5, BP7.
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000155423 SCV000205113 likely benign not specified 2015-03-31 criteria provided, single submitter clinical testing c.1108+9_1108+21del in intron 10 of RAF1: This variant is not expected to have c linical significance because it does not alter an amino acid residue, is not loc ated within the splice consensus sequence, and splice prediction models do not s uggest an impact to splicing.
GeneDx RCV000159065 SCV000209007 benign Rasopathy 2014-08-07 criteria provided, single submitter clinical testing The variant is found in NOONAN panel(s).
Invitae RCV000159065 SCV000659050 likely benign Rasopathy 2020-10-28 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000587828 SCV000698120 benign not provided 2016-03-14 criteria provided, single submitter clinical testing Variant summary: Variant is a deletion of 13 nucleotides located in an intronic region not widely known to affect splicing. 4/5 in silico tools predict the variant not to have an effect on splicing along with mutation taster predicting the variant to be a polymorphism. It was predominantly observed in the Non-Finnish European cohort of the ExAC project at an allele frequency of 0.08% which exceeds the maximal expected allele frequency of a disease causing RAF1 (0.0025%) allele by 32 times, indicating neutrality. The variant has not, to our knowledge, been reported in affected individuals via publications and nor evaluated for functional impact by in vivo/vitro studies. Clinical diagnostic laboratories classify variant as Likely Benign/Benign via ClinVar (without evidence to independently evaluate). Considering the high prevalence of the variant in the general population, this variant was classified as Benign.
St. Jude Clinical Genomics Lab, St. Jude Children's Research Hospital RCV000761098 SCV000891013 benign Noonan syndrome 2020-09-22 criteria provided, single submitter clinical testing The c.1168+9_1168+21del splice region variant has a frequency of 0.0003465 (98 of 282,788 alleles) in gnomAD v2.1.1 with a maximum allele frequency of 0.0006814 (88 of 129,138) in the European non-Finnish population (http://gnomad.broadinstitute.org). This is a high enough frequency to be classified as benign based on thresholds defined by the ClinGen RASopathy Expert Panel for autosomal dominant RASopathy variants (BA1). This variant is not predicted to impact splicing (BP7). This variant has been classified as benign by the ClinGen RASopathy Variant Curation Expert Panel with additional unpublished patient data (SCV000616427.3). In summary, this variant meets criteria to be classified as benign based on the ACMG/AMP criteria, as specified by the ClinGen RASopathy Variant Curation Expert Panel (PMID:29493581): BA1, BP7.

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