rs3789806

Positions:

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_004333.6(BRAF):c.1992+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_004333.6 intron

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9O:1

Conservation

PhyloP100: 0.313

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 -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 [Likely_benign]. Clinvar id is 40393.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-140749271-C-G is described in Lovd as [Benign].

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/exons	MANE	Protein	UniProt
BRAF	NM_001374258.1 linkuse as main transcript	c.2112+16G>C		intron_variant		ENST00000644969.2	NP_001361187.1
BRAF	NM_004333.6 linkuse as main transcript	c.1992+16G>C		intron_variant		ENST00000646891.2	NP_004324.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
BRAF	ENST00000644969.2 linkuse as main transcript	c.2112+16G>C		intron_variant			NM_001374258.1	ENSP00000496776
BRAF	ENST00000646891.2 linkuse as main transcript	c.1992+16G>C		intron_variant			NM_004333.6	ENSP00000493543	P4

Frequencies

GnomAD3 genomes

AF:

0.298

AC:

45280

AN:

151876

Hom.:

10759

Cov.:

show subpopulations

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

GnomAD3 exomes

AF:

0.199

AC:

49747

AN:

250290

Hom.:

7572

AF XY:

0.199

AC XY:

26914

AN XY:

135304

show subpopulations

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 SAS exome

AF:

0.313

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.:

AF XY:

0.167

AC XY:

121127

AN XY:

725174

show subpopulations

Gnomad4 AFR exome

AF:

0.680

Gnomad4 AMR exome

AF:

0.109

Gnomad4 ASJ exome

AF:

0.206

Gnomad4 EAS exome

AF:

0.156

Gnomad4 SAS exome

AF:

0.313

Gnomad4 FIN exome

AF:

0.142

Gnomad4 NFE exome

AF:

0.136

Gnomad4 OTH exome

AF:

0.195

GnomAD4 genome

AF:

0.299

AC:

45378

AN:

151994

Hom.:

10808

Cov.:

AF XY:

0.296

AC XY:

21990

AN XY:

74278

show subpopulations

Gnomad4 AFR

AF:

0.665

Gnomad4 AMR

AF:

0.180

Gnomad4 ASJ

AF:

0.198

Gnomad4 EAS

AF:

0.174

Gnomad4 SAS

AF:

0.309

Gnomad4 FIN

AF:

0.153

Gnomad4 NFE

AF:

0.142

Gnomad4 OTH

AF:

0.268

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:9Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:5

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
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	Apr 25, 2016	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% -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Aug 12, 2019	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. -
Benign, no assertion criteria provided	clinical testing	Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center	Jan 15, 2015	- -

RASopathy

Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -

not provided

Benign:1Other:1

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
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. -

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

Likely benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Dec 12, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.89

CADD

Benign

DANN

Benign

0.50

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