7-140749271-C-G

Variant names:

• chr7-140749271-C-G
• rs3789806
• NM_001374258.1:c.2112+16G>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001374258.1(BRAF):​c.2112+16G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.176 in 1,609,598 control chromosomes in the GnomAD database, including 37,044 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.30 (10808 hom., cov: 32)
  • Exomes 𝑓: 0.16 (26236 hom.)
• Consequence: BRAF NM_001374258.1 intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9 O:1
• Conservation: PhyloP100: 0.313
• Publications: 17 publications found

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 Gene-Disease associations (from GenCC):

• cardiofaciocutaneous syndrome

  Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: ClinGen, Orphanet
• cardiofaciocutaneous syndrome 1

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), PanelApp Australia, Ambry Genetics, G2P, Genomics England PanelApp
• LEOPARD syndrome 3

  Inheritance: AD Classification: DEFINITIVE, STRONG, LIMITED Submitted by: G2P, Labcorp Genetics (formerly Invitae), Ambry Genetics, Genomics England PanelApp
• Noonan syndrome 7

  Inheritance: AD Classification: DEFINITIVE, STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), PanelApp Australia, G2P, Ambry Genetics, Genomics England PanelApp
• Noonan syndrome

  Inheritance: AD Classification: MODERATE Submitted by: ClinGen
• Noonan syndrome with multiple lentigines

  Inheritance: AD Classification: SUPPORTIVE, LIMITED Submitted by: ClinGen, Orphanet
• anaplastic astrocytoma

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics
• Costello syndrome

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.89).
• BP6: Variant 7-140749271-C-G is Benign according to our data. Variant chr7-140749271-C-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 40393.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.658 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
BRAF	NM_001374258.1	c.2112+16G>C		intron_variant	Intron 17 of 19	ENST00000644969.2	NP_001361187.1
BRAF	NM_004333.6	c.1992+16G>C		intron_variant	Intron 16 of 17	ENST00000646891.2	NP_004324.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
BRAF	ENST00000644969.2	c.2112+16G>C		intron_variant	Intron 17 of 19		NM_001374258.1	ENSP00000496776.1
BRAF	ENST00000646891.2	c.1992+16G>C		intron_variant	Intron 16 of 17		NM_004333.6	ENSP00000493543.1

Frequencies

GnomAD3 genomes AF: 0.298 AC: 45280 AN: 151876 Hom.: 10759 Cov.: 32

Gnomad AFR AF: 0.664

Gnomad AMI AF: 0.104

Gnomad AMR AF: 0.181

Gnomad ASJ AF: 0.198

Gnomad EAS AF: 0.174

Gnomad SAS AF: 0.310

Gnomad FIN AF: 0.153

Gnomad MID AF: 0.304

Gnomad NFE AF: 0.142

Gnomad OTH AF: 0.267

GnomAD2 exomes AF: 0.199 AC: 49747 AN: 250290 AF XY: 0.199

Gnomad AFR exome AF: 0.674

Gnomad AMR exome AF: 0.0994

Gnomad ASJ exome AF: 0.205

Gnomad EAS exome AF: 0.186

Gnomad FIN exome AF: 0.149

Gnomad NFE exome AF: 0.142

Gnomad OTH exome AF: 0.179

GnomAD4 exome AF: 0.163 AC: 237989 AN: 1457604 Hom.: 26236 Cov.: 32 AF XY: 0.167 AC XY: 121127 AN XY: 725174

African (AFR) AF: 0.680 AC: 22655 AN: 33324

American (AMR) AF: 0.109 AC: 4878 AN: 44640

Ashkenazi Jewish (ASJ) AF: 0.206 AC: 5361 AN: 26064

East Asian (EAS) AF: 0.156 AC: 6159 AN: 39540

South Asian (SAS) AF: 0.313 AC: 26966 AN: 86054

European-Finnish (FIN) AF: 0.142 AC: 7570 AN: 53248

Middle Eastern (MID) AF: 0.283 AC: 1175 AN: 4146

European-Non Finnish (NFE) AF: 0.136 AC: 151504 AN: 1110504

Other (OTH) AF: 0.195 AC: 11721 AN: 60084

GnomAD4 genome AF: 0.299 AC: 45378 AN: 151994 Hom.: 10808 Cov.: 32 AF XY: 0.296 AC XY: 21990 AN XY: 74278

African (AFR) AF: 0.665 AC: 27556 AN: 41456

American (AMR) AF: 0.180 AC: 2753 AN: 15266

Ashkenazi Jewish (ASJ) AF: 0.198 AC: 687 AN: 3468

East Asian (EAS) AF: 0.174 AC: 900 AN: 5168

South Asian (SAS) AF: 0.309 AC: 1488 AN: 4818

European-Finnish (FIN) AF: 0.153 AC: 1612 AN: 10568

Middle Eastern (MID) AF: 0.306 AC: 90 AN: 294

European-Non Finnish (NFE) AF: 0.142 AC: 9632 AN: 67936

Other (OTH) AF: 0.268 AC: 565 AN: 2108

Alfa AF: 0.125 Hom.: 340

Bravo AF: 0.312

Asia WGS AF: 0.280 AC: 974 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:9 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:5

Aug 12, 2019

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

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: BRAF c.1992+16G>C alters a non-conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. 5/5 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 0.2 in 250290 control chromosomes, predominantly at a frequency of 0.67 within the African or African-American subpopulation in the gnomAD database, including 3698 homozygotes. Therefore, suggesting the variant is the major allele in population(s) of African American origin. Three ClinVar submissions (evaluation after 2014) cite the variant as benign. Based on the evidence outlined above, the variant was classified as benign.

Apr 25, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Frequency in ESP (all): 4109/13006=31.59%

Jan 15, 2015

Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

May 19, 2015

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

RASopathy Benign:2

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

not provided Benign:1 Other: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.

Lung cancer;C0346629:Colorectal cancer;C1835047:Melanoma, cutaneous malignant, susceptibility to, 1;C3150970:Noonan syndrome 7;C3150971:LEOPARD syndrome 3;C4551602:Noonan syndrome 1;CN029449:Cardiofaciocutaneous syndrome 1 Benign:1

Dec 12, 2021

Fulgent Genetics, Fulgent Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	12
DANN	Benign	0.50
PhyloP100		0.31
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs3789806; hg19: chr7-140449071; COSMIC: COSV56062530;