rs9648696

Variant names:

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BA1

This summary comes from the ClinGen Evidence Repository: The filtering allele frequency of the c.1929A>G (p.Gly643=) variant in the BRAF gene is 66.117% (6984/10356) of African chromosomes by the Exome Aggregation Consortium, which is a high enough frequency to be classified as benign based on thresholds defined by the ClinGen RASopathy Expert Panel (BA1; PMID:29493581) LINK:https://erepo.genome.network/evrepo/ui/classification/CA135110/MONDO:0021060/004

Frequency

Genomes: 𝑓 0.30 ( 10970 hom., cov: 32)

Exomes 𝑓: 0.17 ( 26947 hom. )

Consequence

BRAF
NM_004333.6 synonymous

Scores

Clinical Significance

Benign reviewed by expert panel B:14O:1

Conservation

PhyloP100: 1.58

Variant links:

Genes affected

BRAF (HGNC:1097): (B-Raf proto-oncogene, serine/threonine kinase) This gene encodes a protein belonging to the RAF family of serine/threonine protein kinases. This protein plays a role in regulating the MAP kinase/ERK signaling pathway, which affects cell division, differentiation, and secretion. Mutations in this gene, most commonly the V600E mutation, are the most frequently identified cancer-causing mutations in melanoma, and have been identified in various other cancers as well, including non-Hodgkin lymphoma, colorectal cancer, thyroid carcinoma, non-small cell lung carcinoma, hairy cell leukemia and adenocarcinoma of lung. Mutations in this gene are also associated with cardiofaciocutaneous, Noonan, and Costello syndromes, which exhibit overlapping phenotypes. A pseudogene of this gene has been identified on the X chromosome. [provided by RefSeq, Aug 2017]

BRAF links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -8 ACMG points.

BA1

For more information check the summary or visit ClinGen Evidence Repository.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
BRAF	NM_001374258.1 link	c.2049A>G	p.Gly683Gly	synonymous_variant	Exon 17 of 20	ENST00000644969.2	NP_001361187.1
BRAF	NM_004333.6 link	c.1929A>G	p.Gly643Gly	synonymous_variant	Exon 16 of 18	ENST00000646891.2	NP_004324.2	P15056

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
BRAF	ENST00000644969.2 link	c.2049A>G	p.Gly683Gly	synonymous_variant	Exon 17 of 20		NM_001374258.1	ENSP00000496776.1		A0A2R8Y8E0
BRAF	ENST00000646891.2 link	c.1929A>G	p.Gly643Gly	synonymous_variant	Exon 16 of 18		NM_004333.6	ENSP00000493543.1		P15056

Frequencies

GnomAD3 genomes

AF:

0.301

AC:

45688

AN:

151904

Hom.:

10921

Cov.:

show subpopulations

Gnomad AFR

AF:

0.669

Gnomad AMI

AF:

0.104

Gnomad AMR

AF:

0.183

Gnomad ASJ

AF:

0.203

Gnomad EAS

AF:

0.175

Gnomad SAS

AF:

0.313

Gnomad FIN

AF:

0.152

Gnomad MID

AF:

0.323

Gnomad NFE

AF:

0.144

Gnomad OTH

AF:

0.275

GnomAD3 exomes

AF:

0.201

AC:

50505

AN:

250720

Hom.:

7760

AF XY:

0.202

AC XY:

27349

AN XY:

135540

show subpopulations

Gnomad AFR exome

AF:

0.680

Gnomad AMR exome

AF:

0.103

Gnomad ASJ exome

AF:

0.210

Gnomad EAS exome

AF:

0.187

Gnomad SAS exome

AF:

0.314

Gnomad FIN exome

AF:

0.149

Gnomad NFE exome

AF:

0.145

Gnomad OTH exome

AF:

0.184

GnomAD4 exome

AF:

0.165

AC:

241653

AN:

1460534

Hom.:

26947

Cov.:

AF XY:

0.169

AC XY:

123032

AN XY:

726608

show subpopulations

Gnomad4 AFR exome

AF:

0.686

Gnomad4 AMR exome

AF:

0.113

Gnomad4 ASJ exome

AF:

0.211

Gnomad4 EAS exome

AF:

0.156

Gnomad4 SAS exome

AF:

0.315

Gnomad4 FIN exome

AF:

0.143

Gnomad4 NFE exome

AF:

0.138

Gnomad4 OTH exome

AF:

0.199

GnomAD4 genome

AF:

0.301

AC:

45786

AN:

152022

Hom.:

10970

Cov.:

AF XY:

0.299

AC XY:

22214

AN XY:

74346

show subpopulations

Gnomad4 AFR

AF:

0.669

Gnomad4 AMR

AF:

0.183

Gnomad4 ASJ

AF:

0.203

Gnomad4 EAS

AF:

0.175

Gnomad4 SAS

AF:

0.312

Gnomad4 FIN

AF:

0.152

Gnomad4 NFE

AF:

0.144

Gnomad4 OTH

AF:

0.276

Alfa

AF:

0.221

Hom.:

2667

Bravo

AF:

0.316

Asia WGS

AF:

0.279

AC:

972

AN:

3478

EpiCase

AF:

0.161

EpiControl

AF:

0.162

ClinVar

Significance: Benign

Submissions summary: Benign:14Other:1

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

not specified

Benign:5

Nov 16, 2017

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: The BRAF c.1929A>G (p.Gly643Gly) variant involves the alteration of a nucleotide, resulting in a synonymous change. One in silico tool predicts a polymorphism outcome for this variant. 5/5 splice prediction tools predict no significant impact on normal splicing. ESE finder predicts that this variant does not affect any ESE site. However, these predictions have yet to be confirmed by functional studies. This variant was found in 25661/120836 control chromosomes at a frequency of 0.2123622, which is approximately 84945 times the estimated maximal expected allele frequency of a pathogenic BRAF variant (0.0000025), suggesting this variant is likely a benign polymorphism. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as benign. Taken together, this variant is classified as benign. -

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 15, 2015

Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

May 19, 2015

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Dec 03, 2007

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

RASopathy

Benign:4

Baylor Genetics

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Variant classified using ACMG guidelines -

Apr 18, 2017

ClinGen RASopathy Variant Curation Expert Panel

Significance: Benign

Review Status: reviewed by expert panel

Collection Method: curation

The filtering allele frequency of the c.1929A>G (p.Gly643=) variant in the BRAF gene is 66.117% (6984/10356) of African chromosomes by the Exome Aggregation Consortium, which is a high enough frequency to be classified as benign based on thresholds defined by the ClinGen RASopathy Expert Panel (BA1; PMID:29493581) -

Jan 24, 2012

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The variant is found in NOONAN panel(s). -

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided

Benign:2Other:1

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

GenomeConnect, ClinGen

Significance: not provided

Review Status: no classification provided

Collection Method: phenotyping only

GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant. -

Nov 21, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Noonan syndrome 7

Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

LEOPARD syndrome 3

Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Cardiovascular phenotype

Benign:1

Dec 04, 2018

Ambry Genetics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.49

CADD

Benign

7.9

DANN

Benign

0.74

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over