rs377093637

Positions:

• chr7-140783098-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP2

The NM_004333.6(BRAF):​c.1237G>A​(p.Val413Met) variant causes a missense change. The variant allele was found at a frequency of 0.00000274 in 1,461,784 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000027 (0 hom.)
• Consequence: BRAF NM_004333.6 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:4
• Conservation: PhyloP100: 7.18

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 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), BRAF. . Gene score misZ 3.7208 (greater than the threshold 3.09). Trascript score misZ 4.9447 (greater than threshold 3.09). GenCC has associacion of gene with LEOPARD syndrome 3, anaplastic astrocytoma, Noonan syndrome with multiple lentigines, cardiofaciocutaneous syndrome 1, Noonan syndrome, cardiofaciocutaneous syndrome, Costello syndrome, Noonan syndrome 7.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
BRAF	NM_001374258.1	c.1357G>A	p.Val453Met	missense_variant	11/20	ENST00000644969.2	NP_001361187.1
BRAF	NM_004333.6	c.1237G>A	p.Val413Met	missense_variant	10/18	ENST00000646891.2	NP_004324.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
BRAF	ENST00000644969.2	c.1357G>A	p.Val453Met	missense_variant	11/20		NM_001374258.1	ENSP00000496776.1
BRAF	ENST00000646891.2	c.1237G>A	p.Val413Met	missense_variant	10/18		NM_004333.6	ENSP00000493543.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000796 AC: 2 AN: 251402 Hom.: 0 AF XY: 0.00000736 AC XY: 1 AN XY: 135864

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000274 AC: 4 AN: 1461784 Hom.: 0 Cov.: 30 AF XY: 0.00000138 AC XY: 1 AN XY: 727188

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000224

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.0000113

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.0000165 AC: 2

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

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 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Dec 06, 2021

- -

Noonan syndrome 7 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Feb 14, 2019

The BRAF c.1237G>A (p.Val413Met) variant is a missense variant. A literature search was performed for the gene, cDNA change, and amino acid change. No publications were found based on this search. This variant is found at a frequency of 0.000033 in the South Asian population of the Genome Aggregation Database, but this is based on one allele only in a region of good sequence coverage so the variant is presumed to be rare. Based on the limited evidence, the p.Val413Met variant is classified as a variant of uncertain significance for Noonan syndrome. -

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Oct 20, 2011

The Val413Met variant has not been reported in the literature nor identified by our laboratory in over 1,300 individuals. Valine (Val) at position 413 is highly conserved across evolutionarily distant species, suggesting that a change to th e amino acid may not be tolerated. Computational analyses (PolyPhen2, SIFT, Ali gnGVGD) do not provide strong support for or against pathogenicity; however, the accuracy of these tools is unknown. In the absence of additional information, s uch as control studies, segregation data, or functional analyses, the clinical s ignificance of this variant cannot be determined at this time. -

RASopathy Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Oct 13, 2023

This sequence change replaces valine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 413 of the BRAF protein (p.Val413Met). This variant is present in population databases (rs377093637, gnomAD 0.003%). This variant has not been reported in the literature in individuals affected with BRAF-related conditions. ClinVar contains an entry for this variant (Variation ID: 44799). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on BRAF protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Uncertain	0.054	T
BayesDel_noAF	Uncertain	-0.060
CADD	Pathogenic	29
DANN	Uncertain	1.0
DEOGEN2	Benign	0.39	.;.;T;.
Eigen	Uncertain	0.67
Eigen_PC	Pathogenic	0.72
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	0.99	D;D;D;D
M_CAP	Benign	0.059	D
MetaRNN	Uncertain	0.57	D;D;D;D
MetaSVM	Benign	-0.31	T
MutationAssessor	Benign	1.8	.;.;L;.
PrimateAI	Pathogenic	0.90	D
REVEL	Uncertain	0.29
Polyphen		1.0	.;.;D;.
MVP		0.69
MPC		1.5
ClinPred		0.65	D
GERP RS		5.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.16
gMVP		0.53

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: rs377093637; hg19: chr7-140482898; COSMIC: COSV99072600; COSMIC: COSV99072600;