chr3-12600207-A-G
Variant summary
Our verdict is Benign. Variant got -9 ACMG points: 3P and 12B. PM1PP2BP4_StrongBP6_StrongBS2
The NM_002880.4(RAF1):c.935T>C(p.Val312Ala) variant causes a missense change. The variant allele was found at a frequency of 0.0000843 in 1,614,054 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V312M) has been classified as Likely benign.
Frequency
Consequence
NM_002880.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Benign. Variant got -9 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
RAF1 | NM_002880.4 | c.935T>C | p.Val312Ala | missense_variant | 9/17 | ENST00000251849.9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
RAF1 | ENST00000251849.9 | c.935T>C | p.Val312Ala | missense_variant | 9/17 | 1 | NM_002880.4 | P3 |
Frequencies
GnomAD3 genomes ? AF: 0.0000920 AC: 14AN: 152172Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.000151 AC: 38AN: 251364Hom.: 0 AF XY: 0.000162 AC XY: 22AN XY: 135886
GnomAD4 exome AF: 0.0000835 AC: 122AN: 1461882Hom.: 0 Cov.: 32 AF XY: 0.0000990 AC XY: 72AN XY: 727244
GnomAD4 genome ? AF: 0.0000920 AC: 14AN: 152172Hom.: 0 Cov.: 33 AF XY: 0.000108 AC XY: 8AN XY: 74316
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 | Mar 26, 2018 | Variant summary: RAF1 c.935T>C (p.Val312Ala) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00014 in 277138 control chromosomes. The observed variant frequency is approximately 5.77 fold above 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 benign. c.935T>C has been reported in the literature in individuals affected with Noonan Syndrome and Related Conditions. These reports do not provide unequivocal conclusions about an association of the variant with Noonan Syndrome and Related Conditions. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation (1 likely benign, 2 VUS). 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 | Dec 05, 2013 | The Val312Ala variant in RAF1 has not been previously reported in other families with clinical features of Noonan spectrum disorders, but has been identified in 1/8600 European American chromosomes by the NHLBI Exome Sequencing Project (htt p://evs.gs.washington.edu/EVS). Of note, another variant at this position, Val31 2Gly, has been identified in one fetus with abnormal ultrasound findings and a n ormal karyotype (Croonen 2013). Valine (Val) at position 312 is not conserved in mammals or across evolutionarily distant species, and several mammals and other species (including cow, sheep, antelope, and fish species) have an alanine (Ala ) at this position, suggesting that this change may be tolerated. Other computat ional analyses (biochemical amino acid properties, AlignGVGD, PolyPhen2, and SIF T) suggest that the Val312Ala variant may not impact the protein. In summary, ad ditional information is needed to fully assess the clinical significance of the Val312Ala variant. - |
RASopathy Uncertain:1Benign:1
Uncertain significance, reviewed by expert panel | curation | ClinGen RASopathy Variant Curation Expert Panel | Apr 03, 2017 | The c.935T>C p.Val312Ala variant has been identified in 2 probands with clinical features of RASopathies (PS4 not met; GeneDx, Partners LMM internal data; GTR ID's: 26957, 21766; ClinVar SCV000200036.4; SCV000209006.12). Computational prediction tools and conservation analysis suggest that the p.Val312Ala variant does not impact the protein (BP4). In summary, the clinical significance of the p.Val312Ala variant is uncertain. RASopathy-specific ACMG/AMP criteria applied (PMID:29493581): BP4. - |
Likely benign, criteria provided, single submitter | clinical testing | Invitae | Jan 31, 2024 | - - |
Hypertrophic cardiomyopathy 1 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute | Dec 30, 2019 | - - |
not provided Benign:1
Likely benign, criteria provided, single submitter | clinical testing | GeneDx | Feb 01, 2021 | Observed in a newborn with a suspected Noonan spectrum disorder in published literature (Hakami et al., 2016); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 31032133, 27974047, 26918529) - |
Cardiovascular phenotype Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Ambry Genetics | Jun 21, 2019 | 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