rs201937982
Variant summary
Our verdict is Benign. Variant got -8 ACMG points: 2P and 10B. PM2BP4_StrongBP6BP7BS2
The NM_002880.4(RAF1):āc.321T>Cā(p.Gly107=) variant causes a splice region, synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000346 in 1,445,956 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Consequence
NM_002880.4 splice_region, synonymous
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Benign. Variant got -8 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
RAF1 | NM_002880.4 | c.321T>C | p.Gly107= | splice_region_variant, synonymous_variant | 4/17 | ENST00000251849.9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
RAF1 | ENST00000251849.9 | c.321T>C | p.Gly107= | splice_region_variant, synonymous_variant | 4/17 | 1 | NM_002880.4 | P3 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD3 exomes AF: 0.00000796 AC: 2AN: 251270Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 135822
GnomAD4 exome AF: 0.00000346 AC: 5AN: 1445956Hom.: 0 Cov.: 29 AF XY: 0.00000139 AC XY: 1AN XY: 720374
GnomAD4 genome ? Cov.: 32
ClinVar
Submissions by phenotype
not specified Uncertain:1Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Sep 08, 2021 | Variant summary: RAF1 c.321T>C (p.Gly107Gly) alters a conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. 4/4 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 8e-06 in 251270 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.321T>C in individuals affected with Noonan Syndrome and no experimental evidence demonstrating its impact on protein function have been reported. A co-occurrence with a pathogenic variant has been reported (SOS1 c.1656G>C, p.Arg552Ser; Internal testing), providing supporting evidence for a benign role. A ClinVar submitter (evaluation after 2014) cites the variant as likely benign. Based on the evidence outlined above, the variant was classified as likely benign. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Sep 02, 2010 | Variant classified as Uncertain Significance - Favor Benign. The Gly107Gly varia nt has not been previously reported in the literature or been identified in our laboratory. This variant does not result in an amino acid change, but it does al ter the first base of exon 4 which could have an effect on splicing. Splicing va riants have not been reported as part of the mutation spectrum for RAF1, which a re typically gain-of-function. - |
RASopathy Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Jul 07, 2023 | 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. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant is not likely to affect RNA splicing. ClinVar contains an entry for this variant (Variation ID: 165010). This variant has not been reported in the literature in individuals affected with RAF1-related conditions. This variant is present in population databases (rs201937982, gnomAD 0.006%). This sequence change affects codon 107 of the RAF1 mRNA. It is a 'silent' change, meaning that it does not change the encoded amino acid sequence of the RAF1 protein. It affects a nucleotide within the consensus splice site. - |
not provided Benign:1
Likely benign, criteria provided, single submitter | clinical testing | GeneDx | Jul 30, 2018 | - - |
Cardiovascular phenotype Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Ambry Genetics | Aug 02, 2021 | This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at