rs113488022

chr7-140753336-A-Cchr7-140753336-A-Gchr7-140753336-A-T

• Frequency: Genomes: not found (cov: 32)
• Consequence: BRAF NM_001374258 missense
• Clinical Significance: Pathogenic reviewed by expert panel P:3 U:1 O:1
• Conservation: PhyloP100: 9.24

ACMG classification

Verdict is Pathogenic. Variant got 16 ACMG points.

• PM1: In a hotspot region, there are 10 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 4 uncertain in NM_001374258
• PM2: Very rare variant; Number of alleles below threshold, Median coverage is 32.
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr7-140753336-A-T is described in ClinVar as [Pathogenic, drug_response, other]. Clinvar id is 13961. Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP2: Missense variant where missense usually causes diseases, BRAF
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.909
• PP5: Variant 7:140753336-A>C is Pathogenic according to our data. Variant chr7-140753336-A-C is described in ClinVar as [Pathogenic]. Clinvar id is 40389. Status of the report is reviewed_by_expert_panel, 3 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
BRAF	NM_001374258.1	c.1919T>G	p.Val640Gly	missense_variant	16/20	ENST00000644969.2
BRAF	NM_004333.6	c.1799T>G	p.Val600Gly	missense_variant	15/18	ENST00000646891.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BRAF	ENST00000644969.2	c.1919T>G	p.Val640Gly	missense_variant	16/20		NM_001374258.1
BRAF	ENST00000646891.2	c.1799T>G	p.Val600Gly	missense_variant	15/18		NM_004333.6	A1

Frequencies

GnomAD3 genomes Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:3Uncertain:1Other:1

Revision: reviewed by expert panel

LINK:

Submissions by phenotype

RASopathy Pathogenic:2

Pathogenic, reviewed by expert panel	curation	ClinGen RASopathy Variant Curation Expert Panel	Jun 25, 2020	The c.1799T>G (p.Val600Gly) variant in BRAF is absent from gnomAD (PM2). It has been identified in one individual with Cardiofaciocutaneous syndrome (PS4_Supporting; PMID: 20735442). It has also been reported in the literature as an unconfirmed de novo occurrence (PM6; GeneDx internal communication). In vitro functional studies provide some evidence that the p.Val600Gly variant may impact protein function (PS3; PMID: 20735442). Furthermore, the variant is in a location that has been defined by the ClinGen RASopathy Expert Panel to be a mutational hotspot or domain of BRAF (PM1; PMID 29493581). Computational prediction tools and conservation analysis suggest that the p.Val600Gly variant may impact the protein (PP3). Finally, the variant is located in BRAF, 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): PS3, PM1, PM2, PM6, PS4_Supporting, PP3, PP2. -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Aug 30, 2022	This sequence change replaces valine, which is neutral and non-polar, with glycine, which is neutral and non-polar, at codon 600 of the BRAF protein (p.Val600Gly). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with cardio-facio-cutaneous syndrome (PMID: 20735442). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 40389). 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. For these reasons, this variant has been classified as Pathogenic. -

Melanoma Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

Database of Curated Mutations (DoCM)

Oct 02, 2014

- -

not provided Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

Department of Pathology and Laboratory Medicine, Sinai Health System

-

- -

Cardio-facio-cutaneous syndrome Other:1

not provided, no assertion provided

literature only

GeneReviews

-

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.98

BayesDel_addAF

Pathogenic

0.41

D

BayesDel_noAF

Pathogenic

0.36

Cadd

Pathogenic

28

Dann

Uncertain

1.0

Eigen

Uncertain

0.54

Eigen_PC

Uncertain

0.61

FATHMM_MKL

Pathogenic

0.99

D

LIST_S2

Uncertain

0.87

D;D;D;D

M_CAP

Uncertain

0.18

D

MetaRNN

Pathogenic

0.91

D;D;D;D

MetaSVM

Benign

-0.37

T

MutationTaster

Benign

1.0

D

PrimateAI

Pathogenic

0.84

D

Polyphen

0.82

.;.;P;.

MutPred

0.75

Loss of stability (P = 0.0081);.;Loss of stability (P = 0.0081);.;

MVP

0.99

MPC

1.8

ClinPred

1.0

D

GERP RS

5.7

Varity_R

0.98

gMVP

0.96

Splicing

Find out SpliceAI and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs113488022; hg19: chr7-140453136; COSMIC: COSV56080151;