rs9648696

Positions:

• chr7-140749350-T-C

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
• Clinical Significance: Benign reviewed by expert panel B:14 O:1
• Conservation: PhyloP100: 1.58

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]

ACMG classification

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/exons	MANE	Protein	UniProt
BRAF	NM_001374258.1	c.2049A>G	p.Gly683=	synonymous_variant	17/20	ENST00000644969.2	NP_001361187.1
BRAF	NM_004333.6	c.1929A>G	p.Gly643=	synonymous_variant	16/18	ENST00000646891.2	NP_004324.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
BRAF	ENST00000644969.2	c.2049A>G	p.Gly683=	synonymous_variant	17/20		NM_001374258.1	ENSP00000496776
BRAF	ENST00000646891.2	c.1929A>G	p.Gly643=	synonymous_variant	16/18		NM_004333.6	ENSP00000493543	P4

Frequencies

GnomAD3 genomes AF: 0.301 AC: 45688 AN: 151904 Hom.: 10921 Cov.: 32

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

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.: 32 AF XY: 0.169 AC XY: 123032 AN XY: 726608

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.: 32 AF XY: 0.299 AC XY: 22214 AN XY: 74346

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:14 Other:1

Revision: reviewed by expert panel

Submissions by phenotype

not specified Benign:5

Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Nov 16, 2017	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. -
Benign, no assertion criteria provided	clinical testing	Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center	Jan 15, 2015	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	May 19, 2015	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Dec 03, 2007	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

RASopathy Benign:4

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 24, 2012	The variant is found in NOONAN panel(s). -
Benign, no assertion criteria provided	clinical testing	Baylor Genetics	-	Variant classified using ACMG guidelines -
Benign, reviewed by expert panel	curation	ClinGen RASopathy Variant Curation Expert Panel	Apr 18, 2017	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) -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -

not provided Benign:2 Other:1

Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 29, 2023	- -
not provided, no classification provided	phenotyping only	GenomeConnect, ClinGen	-	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. -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Noonan syndrome 7 Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

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

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

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. -

Cardiovascular phenotype Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 04, 2018

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

Other links and lift over

dbSNP: rs9648696; hg19: chr7-140449150; COSMIC: COSV56058907;