7-140834676-C-T

Position:

chr7-140834676-C-T

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 1P and 6B. PP2BP4_ModerateBS2

The NM_001374258.1(BRAF):c.437G>A(p.Arg146Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000929 in 1,614,116 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000089 ( 0 hom. )

Consequence

BRAF
NM_001374258.1 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:5B:1

Conservation

PhyloP100: 7.62

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 Likely_benign. Variant got -5 ACMG points.

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 4.9008 (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.

BP4

Computational evidence support a benign effect (MetaRNN=0.15396866).

BS2

High AC in GnomAdExome4 at 13 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
BRAF	NM_001374258.1 linkuse as main transcript	c.437G>A	p.Arg146Gln	missense_variant	3/20	ENST00000644969.2	NP_001361187.1
BRAF	NM_004333.6 linkuse as main transcript	c.437G>A	p.Arg146Gln	missense_variant	3/18	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.437G>A	p.Arg146Gln	missense_variant	3/20		NM_001374258.1	ENSP00000496776
BRAF	ENST00000646891.2 linkuse as main transcript	c.437G>A	p.Arg146Gln	missense_variant	3/18		NM_004333.6	ENSP00000493543	P4

Frequencies

GnomAD3 genomes

AF:

0.0000131

AC:

AN:

152150

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000318

AC:

AN:

251440

Hom.:

AF XY:

0.0000221

AC XY:

AN XY:

135890

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000202

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:

0.00000889

AC:

AN:

1461848

Hom.:

Cov.:

AF XY:

0.00000825

AC XY:

AN XY:

727214

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.000179

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000232

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000270

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000131

AC:

AN:

152268

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74444

show subpopulations

Gnomad4 AFR

AF:

0.0000241

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000207

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000329

Hom.:

Bravo

AF:

0.0000302

ExAC

AF:

0.0000165

AC:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.00

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:5Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not specified

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Feb 25, 2020	The p.Arg146Gln variant in BRAF has been reported in at least one individual with Noonan syndrome and related conditions (Leach 2018), but has also been identified in 0.02% (7/34592) of Latino chromosomes by gnomAD (http://gnomad.broadinstitute.org). This variant has been reported as a variant of uncertain significance in ClinVar (Variation ID 372564). Computational prediction tools and conservation analyses do not provide strong support for or against an impact to the protein. In summary, the clinical significance of this variant is uncertain. ACMG/AMP Criteria applied: None. -
Uncertain significance, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Oct 05, 2017	- -

Lung carcinoma;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

Oct 31, 2018

- -

Cardiofaciocutaneous syndrome 1

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Baylor Genetics

Jun 26, 2020

This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868]. -

RASopathy

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Dec 06, 2023

This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 146 of the BRAF protein (p.Arg146Gln). This variant is present in population databases (rs557241012, gnomAD 0.02%). This missense change has been observed in individual(s) with clinical features of Noonan syndrome and/or related conditions (PMID: 29907801). ClinVar contains an entry for this variant (Variation ID: 372564). Advanced modeling performed at Invitae incorporating data from internal and/or published experimental studies (Invitae) indicates that this missense variant is not expected to disrupt BRAF function with a negative predictive value of 95%. 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. -

not provided

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

GeneDx

Apr 26, 2021

Missense variants in this gene are often considered pathogenic (Stenson et al., 2014); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 29907801, 30050098) -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.16

BayesDel_addAF

Benign

-0.14

BayesDel_noAF

Benign

-0.16

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Benign

0.35

.;.;T;.;.

Eigen

Uncertain

0.30

Eigen_PC

Uncertain

0.44

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Pathogenic

0.99

D;D;D;D;D

M_CAP

Benign

0.017

MetaRNN

Benign

0.15

T;T;T;T;T

MetaSVM

Benign

-0.68

MutationAssessor

Benign

0.90

.;.;L;.;.

MutationTaster

Benign

1.0

PrimateAI

Uncertain

0.56

PROVEAN

Benign

-0.20

.;.;.;N;.

REVEL

Benign

0.28

Sift

Benign

0.32

.;.;.;T;.

Sift4G

Benign

0.27

.;.;.;T;.

Polyphen

0.70

.;.;P;.;.

Vest4

0.73

MVP

0.68

MPC

1.1

ClinPred

0.21

GERP RS

5.5

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.27

gMVP

0.65

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