3-12604194-G-T
Variant summary
Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM1PM2PP2PS2PS4_Moderate
This summary comes from the ClinGen Evidence Repository: The c.776C>A (p.Ser259Tyr) variant in RAF1 was absent from large population studies (PM2; gnomAD, http://gnomad.broadinstitute.org). It has been reported in 3 probands with clinical features of Noonan syndrome (PS4_Moderate; PMIDs: 31030682, 26918529, GeneDx internal data). In one proband, the variant occurred de novo with parentage confirmation (PS2; PMID:31030682). The c.776C>A (p.Ser259Tyr) variant occurs in the CR2 activation domain of RAF1, which has been defined by the ClinGen RASopathy Expert Panel as a region important for protein function (PM1; PMID 29493581). A different pathogenic missense variant has been previously identified at this codon of RAF1 supporting this residue is critical to the function of the protein (PM5 not applied; ClinVar 40601). The variant is located in RAF1, which has been defined by the ClinGen RASopathy Expert Panel as a gene with a low rate of benign missense variants and pathogenic missense variants are common (PP2; PMID:29493581). In summary, this variant meets criteria to be classified as pathogenic for RASopathies in an autosomal dominant manner. Rasopathy-specific ACMG/AMP criteria applied (PMID:29493581): PM2, PS4_Moderate, PS2, PM1, PP2. LINK:https://erepo.genome.network/evrepo/ui/classification/CA134750/MONDO:0021060/004
Frequency
Consequence
NM_002880.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 11 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD4 exome Cov.: 31
GnomAD4 genome Cov.: 32
ClinVar
Submissions by phenotype
LEOPARD syndrome 2 Pathogenic:1
- -
not provided Pathogenic:1
PS2, PS4_moderate, PM1, PM2, PP2 -
Noonan syndrome 5 Pathogenic:1
ACMG Criteria: PS2, PM1, PM2_P, PM5, PP3, PP5; Variant was found heterozygously in de novo-status by prenatal trio exome sequence analysis. -
RASopathy Pathogenic:1
The c.776C>A (p.Ser259Tyr) variant in RAF1 was absent from large population studies (PM2; gnomAD, http://gnomad.broadinstitute.org). It has been reported in 3 probands with clinical features of Noonan syndrome (PS4_Moderate; PMIDs: 31030682, 26918529, GeneDx internal data). In one proband, the variant occurred de novo with parentage confirmation (PS2; PMID: 31030682). The c.776C>A (p.Ser259Tyr) variant occurs in the CR2 activation domain of RAF1, which has been defined by the ClinGen RASopathy Expert Panel as a region important for protein function (PM1; PMID 29493581). A different pathogenic missense variant has been previously identified at this codon of RAF1 supporting this residue is critical to the function of the protein (PM5 not applied; ClinVar 40601). The variant is located in RAF1, which has been defined by the ClinGen RASopathy Expert Panel as a gene with a low rate of benign missense variants and pathogenic missense variants are common (PP2; PMID: 29493581). In summary, this variant meets criteria to be classified as pathogenic for RASopathies in an autosomal dominant manner. Rasopathy-specific ACMG/AMP criteria applied (PMID:29493581): PM2, PS4_Moderate, PS2, PM1, PP2. -
not specified Uncertain:1
proposed classification - variant undergoing re-assessment, contact laboratory -
Noonan syndrome Uncertain:1
- -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at