chr3-12604200-G-A
Variant summary
The NM_002880.4(RAF1):c.770C>T (p.Ser257Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant is absent from the gnomAD population database at sites with sufficient sequencing coverage. In-silico predictor (REVEL) classifies this variant as likely damaging/oncogenic. Splicing prediction tools (SpliceAI) predict no significant impact on normal splicing. The affected nucleotide is highly conserved across species (PhyloP 100-way vertebrate score: 10.00). Variant has been reported in ClinVar as Pathogenic/Likely Pathogenic (★★★). ClinVar reports functional evidence for this variant: "SCV002521319: Functional studies provide strong evidence of the variant having a damaging effect on the gene or gene product (PMID:17603482, 20052757)." and additional evidence is available in ClinVar. A different missense at the same amino acid position has been reported as Pathogenic/Likely Pathogenic in ClinVar: p.S257T: Likely_pathogenic (ClinVar VariationId 618340, 2 stars) Other variants at the same amino acid position have been reported in ClinVar (not pathogenic): p.S257= (synonymous): Likely_benign (ClinVar VariationId 1112676, 1 star); p.S257W: Conflicting_classifications_of_pathogenicity (ClinVar VariationId 376514) This exact variant is established as oncogenic in: ClinVar, CGI (Cancer Genome Interpreter). The variant position is a cancer hotspot (cancerhotspots.org): 25 samples carry this exact amino acid change out of 50 samples with a variant at this residue. This exact variant is curated in the UniProt human variants database as Uncertain Significance, associated with Noonan syndrome 5 (ns5); it is also listed as a COSMIC curated somatic variant.
Frequency
Consequence
NM_002880.4 missense
Scores
Clinical Significance
Conservation
Publications
- Noonan syndromeInheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: Orphanet, ClinGen
- Noonan syndrome 5Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Genomics England PanelApp, Labcorp Genetics (formerly Invitae), PanelApp Australia, G2P, Ambry Genetics
- dilated cardiomyopathy 1NNInheritance: AD Classification: STRONG, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), PanelApp Australia, Ambry Genetics
- LEOPARD syndrome 2Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae), Genomics England PanelApp, PanelApp Australia
- familial isolated dilated cardiomyopathyInheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
- Noonan syndrome with multiple lentiginesInheritance: AD Classification: SUPPORTIVE, LIMITED Submitted by: Orphanet, ClinGen
- cardiofaciocutaneous syndromeInheritance: AD Classification: NO_KNOWN Submitted by: ClinGen
- Costello syndromeInheritance: AD Classification: NO_KNOWN Submitted by: ClinGen
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Classification according to ACMG Germline Pathogenicity v2019
Our verdict: Pathogenic. The variant received 19 points.
| Apply | Criterion Code & Title / Strength | Rationale / Clinical Context | |
|---|---|---|---|
| PS3Functional studies show damaging effect | Well-established functional study supports damaging effect (PS3); SCV002521319: Functional studies provide strong evidence of the variant having a damaging effect on the gene or gene product (PMID: 17603482, 20052757).; SCV004047601: Experimental studies have shown that this missense change leads to increased activation of MEK, ERK, and ELK in vitro (Razzaque et al., 2007).; SCV006059810: Functional evidence using transfected cells demonstrated that the variant impacts protein function (PMID: 17603482).; SCV000287743: Experimental studies have shown that this missense change affects RAF1 function (PMID: 17603482, 20052757).; SCV000918146: Several publications reported experimental evidence evaluating an impact on protein function, demonstrating increased kinase activity (Razzaque 2007), increased activation of MEK and ERK (Lee 2011) and altered signaling in cardiomyocytes consistent with that observed in cardiac hypertrophy (Dhandapany 2011).; SCV000616378: "In vitro functional studies provide some evidence that the p.Ser257Leu variant may impact protein function (PS3; PMID 17603482)."; SCV000209016: "Published functional studies demonstrate that S257L produces a gain of function effect with higher kinase activity than wild-type protein (Razzaque et al., 2007; Lee et al., 2011)"; SCV001473076: Functional characterization of the p.Ser257Leu variant protein indicates a loss of serine-259 phosphorylation and reduced association with 14-3-3 (Kobayashi 2010).; SCV002496785: PS3:Supporting; SCV005416118: "Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product."; SCV005685102: "kinase assays suggest that this variant results in impaired gene function" [PMID:17603482]; SCV001984841: Functional studies indicate that the p.Ser257Leu produces a gain-of-function effect with higher kinase activity than wild-type protein (PMID: 17603482). | ||
| PM1Mutational hot spot or critical domain | Missense neighbourhood hotspot (≥2 P/LP within ±8 AA, OR ≥ 5 vs. background) — PM1; In-domain: 0 pathogenic, 0 benign rare missense variants.; ±8 AA neighbourhood: 31 pathogenic, 0 benign (OR vs. background: 315.0). | ||
| PM2Absent/extremely low in population databases | Absent from gnomAD (AD/XL gene) — PM2; Absent from gnomAD at well-covered site (MOI: AD/XL) (threshold 0.0001) — PM2 moderate. | ||
| PM5Novel missense at known pathogenic residue | Different pathogenic missense at same AA residue in ClinVar (PM5); ClinVar contains a germline Pathogenic/Likely Pathogenic entry at the same amino acid position with a different amino acid change: p.S257T: Likely_pathogenic (ClinVar VariationId 618340, 2 stars); Other variants at the same amino acid residue (not pathogenic): p.S257= (synonymous): Likely_benign (ClinVar VariationId 1112676, 1 star); p.S257W: Conflicting_classifications_of_pathogenicity (ClinVar VariationId 376514) | ||
| PP3Computational evidence supports damaging effect | Germline meta computational scorer (REVEL/MetaRNN/BayesDel) predicts damaging effect — supporting evidence (PP3); Splicing verdict: not pathogenic.; Germline computational verdict: pathogenic (Supporting). | ||
| PP5Reputable source reports pathogenic | ClinVar ≥3 stars pathogenic — very strong (PP5); ClinVar germline classification: Pathogenic/Likely Pathogenic, 3 star(s). |
Variant Effect in Transcripts
Automated classification analysis was done for transcript: NM_002880.4. You can select a different transcript below to see updated classification assignments.
RefSeq Transcripts
| Sel. | Gene / Transcript | Tags | HGVSc / HGVSp | Effect | Exon rank | Protein / UniProt |
|---|---|---|---|---|---|---|
RAF1 | MANE Select | c.770C>T p.Ser257Leu | missense | Exon 7 of 17 | Prot: NP_002871.1 | |
RAF1 | c.770C>T p.Ser257Leu | missense | Exon 7 of 18 | Prot: NP_001341618.1 UniProt: | ||
RAF1 | c.770C>T p.Ser257Leu | missense | Exon 7 of 17 | Prot: NP_001341619.1 |
Ensembl Transcripts
| Sel. | Gene / Transcript | Tags | HGVSc / HGVSp | Effect | Exon rank | Protein / UniProt |
|---|---|---|---|---|---|---|
RAF1 | TSL:1MANE Select | c.770C>T p.Ser257Leu | missense | Exon 7 of 17 | Prot: ENSP00000251849.4 UniProt: | |
RAF1 | TSL:5 | c.770C>T p.Ser257Leu | missense | Exon 7 of 18 | Prot: ENSP00000401888.2 UniProt: | |
RAF1 | c.770C>T p.Ser257Leu | missense | Exon 7 of 18 | Prot: ENSP00000570441.1 UniProt: |
Frequencies
Allele frequencies (AF), counts (AC/AN), homozygotes and coverage
| Source / population | AF | AC | Hom | AN | Coverage |
|---|---|---|---|---|---|
Global population databases 5 sources | |||||
GnomAD3 genomes | Cov:33 | ||||
GnomAD4 exome | Cov:31 | ||||
GnomAD4 genome | Cov:33 | ||||
TOPMed (Bravo) | AF: 0.00000378 | ||||
ALFA (dbGaP/dbSNP Allele Frequency Aggregator) | AF: 0.00 | AC:0 | Hom:0 | AN:207520 | |
ClinVar
Computational Scores
| Algorithm | Calibrated pred. | Score | Prediction |
|---|---|---|---|
AlphaGenome AVI | Pathogenic | 30 | |
AlphaMissense | Pathogenic | 0.97 | |
BayesDel_addAF | Pathogenic | 0.41 | D |
BayesDel_noAF | Pathogenic | 0.35 | |
CADD | Pathogenic | 28 | |
DANN | Pathogenic | 1.0 | |
DEOGEN2 | Pathogenic | 0.89 | D |
Eigen | Uncertain | 0.56 | |
Eigen_PC | Uncertain | 0.60 | |
FATHMM_MKL | Uncertain | 0.93 | D |
FuncVEP CTI | Pathogenic | 1.0 | |
GPN-Star LLR | N/A | -9.2 | |
GPN-Star score | N/A | 9.2 | |
LIST_S2 | Pathogenic | 0.99 | D |
M_CAP | Uncertain | 0.28 | D |
MetaRNN | Pathogenic | 0.80 | D |
MetaSVM | Uncertain | 0.10 | D |
Mutation Taster | N/A | 0/100 | disease causing (ClinVar) |
MutationAssessor | Pathogenic | 3.0 | M |
PhyloP100 | Pathogenic | 10 | |
popEVE | Benign | -4.2 | |
PrimateAI | Pathogenic | 0.82 | D |
PromoterAI | N/A | -0.044 | Neutral |
PROVEAN | Uncertain | -4.0 | D |
REVEL | Pathogenic | 0.65 | |
Sift | Pathogenic | 0.0 | D |
Sift4G | Uncertain | 0.015 | D |
Varity_R | N/A | 0.89 | |
VESM-3B | Benign | -13 |
Splicing Scores
| Algorithm | Calibrated pred. | Score | Prediction |
|---|---|---|---|
Pangolin (max) | Benign | 0.0 | |
SpliceAI score (max) | Benign | 0.0 | Details are displayed if max score is > 0.2 |
Find out detailed SpliceAI scores and Pangolin per-transcript scores at
MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.