rs397507484
Variant summary
Our verdict is Pathogenic. Variant got 17 ACMG points: 17P and 0B. PM1PM2PM5PP2PP3_ModeratePP5_Very_Strong
The NM_001374258.1(BRAF):c.1922A>T(p.Lys641Ile) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. K641N) has been classified as Likely pathogenic.
Frequency
Consequence
NM_001374258.1 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 17 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
BRAF | NM_001374258.1 | c.1922A>T | p.Lys641Ile | missense_variant | 16/20 | ENST00000644969.2 | |
BRAF | NM_004333.6 | c.1802A>T | p.Lys601Ile | missense_variant | 15/18 | ENST00000646891.2 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
BRAF | ENST00000644969.2 | c.1922A>T | p.Lys641Ile | missense_variant | 16/20 | NM_001374258.1 | |||
BRAF | ENST00000646891.2 | c.1802A>T | p.Lys601Ile | missense_variant | 15/18 | NM_004333.6 | P4 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD4 exome Cov.: 30
GnomAD4 genome ? Cov.: 32
ClinVar
Submissions by phenotype
RASopathy Pathogenic:2
Likely pathogenic, no assertion criteria provided | clinical testing | Baylor Genetics | - | Variant classified using ACMG guidelines - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Nov 12, 2021 | For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Lys601 amino acid residue in BRAF. Other variant(s) that disrupt this residue have been determined to be pathogenic (Invitae). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt BRAF protein function. ClinVar contains an entry for this variant (Variation ID: 40390). This missense change has been observed in individuals with cardiofaciocutaneous syndrome (PMID: 24451042, 28650561). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces lysine, which is basic and polar, with isoleucine, which is neutral and non-polar, at codon 601 of the BRAF protein (p.Lys601Ile). - |
Cardio-facio-cutaneous syndrome Pathogenic:1Other:1
Likely pathogenic, no assertion criteria provided | clinical testing | Service de Génétique Moléculaire, Hôpital Robert Debré | - | - - |
not provided, no classification provided | phenotyping only | GenomeConnect - CFC International | - | Variant interpreted as Pathogenic and reported on 08-23-2017 by Lab or GTR ID 26957. GenomeConnect-CFC International assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. - |
Noonan syndrome 7 Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Neuberg Centre For Genomic Medicine, NCGM | - | The missense variant p.K601I in BRAF (NM_004333.4) has been reported to ClinVar as Likely Pathogenic(de novo in origin). The p.K601I variant is novel (not in any individuals) in gnomAD Exomes and is novel (not in any individuals) in 1000 Genomes. There is a moderate physicochemical difference between lysine and isoleucine. The p.K601I missense variant is predicted to be damaging by both SIFT and PolyPhen2. The lysine residue at codon 601 of BRAF is conserved in all mammalian species. The nucleotide c.1802 in BRAF is predicted conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Uncertain Significance. - |
Cardiofaciocutaneous syndrome 1 Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | 3billion | Mar 22, 2022 | Same or different nucleotide change resulting in same amino acid change has been previously reported to be associated with [GeneName] related disorder (ClinVar ID: VCV000040390, PMID:24451042). The variant has been previously reported as de novo in a similarly affected individual (PMID: 25533962). A different missense change at the same codon has been reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000013966,VCV000041446, PMID:19206169). The variant is located in a mutational hot spot and/or well-established functional domain in which established pathogenic variants have been reported. In silico tool predictions suggest damaging effect of the variant on gene or gene product(REVEL: 0.943>=0.6). A missense variant is a common mechanism associated with Cardiofaciocutaneous syndrome. It is not observed in the gnomAD v2.1.1 dataset. Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline. - |
not provided Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden | May 04, 2022 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at