rs180177042
Variant summary
Our verdict is Pathogenic. Variant got 23 ACMG points: 23P and 0B. PS1_Very_StrongPM2PP2PP3_StrongPP5_Very_Strong
The NM_001374258.1(BRAF):c.2034T>G(p.Asp678Glu) variant causes a missense change involving the alteration of a non-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 Pathogenic (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely pathogenicin ClinVar.
Frequency
Consequence
NM_001374258.1 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 23 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
BRAF | NM_001374258.1 | c.2034T>G | p.Asp678Glu | missense_variant | 17/20 | ENST00000644969.2 | |
BRAF | NM_004333.6 | c.1914T>G | p.Asp638Glu | missense_variant | 16/18 | ENST00000646891.2 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
BRAF | ENST00000644969.2 | c.2034T>G | p.Asp678Glu | missense_variant | 17/20 | NM_001374258.1 | |||
BRAF | ENST00000646891.2 | c.1914T>G | p.Asp638Glu | missense_variant | 16/18 | NM_004333.6 | P4 |
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD4 exome Cov.: 31
GnomAD4 genome Cov.: 32
ClinVar
Submissions by phenotype
not provided Pathogenic:5
Pathogenic, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Nov 01, 2020 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Dec 28, 2022 | Not observed in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; The majority of missense variants in this gene are considered pathogenic [(HGMD]; This variant is associated with the following publications: (PMID: 27171548, 30141192, 23093928, 25525159, 19206169, 18413255, 21063443, 30556322, 32369273, 33040082, 31069529, 34643321) - |
Pathogenic, no assertion criteria provided | clinical testing | Genome Diagnostics Laboratory, University Medical Center Utrecht | - | - - |
Pathogenic, no assertion criteria provided | clinical testing | Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ | - | - - |
Pathogenic, no assertion criteria provided | clinical testing | Genome Diagnostics Laboratory, Amsterdam University Medical Center | - | - - |
Cardiofaciocutaneous syndrome 1 Pathogenic:2
Pathogenic, no assertion criteria provided | clinical testing | Molecular Genetics Laboratory, BC Children's and BC Women's Hospitals | Sep 21, 2018 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Genomic Medicine Lab, University of California San Francisco | Aug 16, 2018 | - - |
Cardio-facio-cutaneous syndrome Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center | Mar 14, 2024 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Aug 27, 2013 | The Asp638Glu variant in BRAF has been reported to have occurred de novo in two individuals with clinical features of Cardio-facio-cutaneous syndrome (Sarkozy 2 009, Kleefstra 2011). Another variant at this nucleotide position resulting in the same amino acid residue change has also been reported in two individuals wit h clinical features of Cardio-facio-cutaneous syndrome including one de novo occ urrence (Sarkozy 2009, Rauen 2006). This variant was not identified in large po pulation studies. Studies have shown that the Asp638Glu variant impacts protein function (Rodriguez-Viciana 2008). In summary, the Asp638Glu variant meets our c riteria to be classified as pathogenic (http://pcpgm.partners.org/LMM) based upo n its de novo occurrence in affected individuals, low allele frequency in the ge neral population, and supporting functional evidence. - |
Inborn genetic diseases Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Jan 05, 2017 | - - |
RASopathy Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Aug 28, 2022 | For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects BRAF function (PMID: 18413255). 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: 162797). This missense change has been observed in individual(s) with cardio-facio-cutaneous syndrome (CFC) and Costello syndrome (PMID: 16804887, 18039235, 22495831). In at least one individual the variant was observed to be de novo. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces aspartic acid, which is acidic and polar, with glutamic acid, which is acidic and polar, at codon 638 of the BRAF protein (p.Asp638Glu). - |
Noonan syndrome 1 Other:1
not provided, no classification provided | phenotyping only | GenomeConnect - CFC International | - | Variant interpreted as Pathogenic and reported on 10-13-2014 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. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at