7-140787575-T-C

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 1P and 20B. PP2BP4_StrongBP6_Very_StrongBS1BS2

The NM_001374258.1(BRAF):c.1150A>G(p.Arg384Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000298 in 1,612,470 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 Benign (★★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R384K) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000059 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000027 ( 0 hom. )

Consequence

BRAF
NM_001374258.1 missense

Scores

Clinical Significance

Benign reviewed by expert panel B:4

Conservation

PhyloP100: 2.53

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:

(HGNC:):

links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -19 ACMG points.

PP2

Missense variant where missense usually causes diseases, BRAF

BP4

Computational evidence support a benign effect (MetaRNN=0.0242441).

BP6

Variant 7-140787575-T-C is Benign according to our data. Variant chr7-140787575-T-C is described in ClinVar as [Benign]. Clinvar id is 448924.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr7-140787575-T-C is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.0000591 (9/152328) while in subpopulation EAS AF= 0.00154 (8/5188). AF 95% confidence interval is 0.000767. There are 0 homozygotes in gnomad4. There are 6 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High AC in GnomAd at 9 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
BRAF	NM_001374258.1 linkuse as main transcript	c.1150A>G	p.Arg384Gly	missense_variant	9/20	ENST00000644969.2
BRAF	NM_004333.6 linkuse as main transcript	c.1150A>G	p.Arg384Gly	missense_variant	9/18	ENST00000646891.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Appris
BRAF	ENST00000644969.2 linkuse as main transcript	c.1150A>G	p.Arg384Gly	missense_variant	9/20	NM_001374258.1
BRAF	ENST00000646891.2 linkuse as main transcript	c.1150A>G	p.Arg384Gly	missense_variant	9/18	NM_004333.6	P4
	ENST00000700122.1 linkuse as main transcript	n.503-6710T>C		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes

AF:

0.0000591

AC:

AN:

152210

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00154

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:

0.000183

AC:

AN:

251312

Hom.:

AF XY:

0.000169

AC XY:

AN XY:

135832

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00250

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000267

AC:

AN:

1460142

Hom.:

Cov.:

AF XY:

0.0000220

AC XY:

AN XY:

726478

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.000859

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

9.00e-7

Gnomad4 OTH exome

AF:

0.0000663

GnomAD4 genome

AF:

0.0000591

AC:

AN:

152328

Hom.:

Cov.:

AF XY:

0.0000805

AC XY:

AN XY:

74492

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00154

Gnomad4 SAS

AF:

0.000207

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000680

Hom.:

Bravo

AF:

0.0000718

ExAC

AF:

0.000132

AC:

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

RASopathy

Benign:2

Benign, reviewed by expert panel	curation	ClinGen RASopathy Variant Curation Expert Panel	Apr 18, 2017	The filtering allele frequency of the c.1150A>G (p.Arg384Gly) variant in the BRAF gene is 0.116% (16/8646) of East Asian 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) -
Likely benign, criteria provided, single submitter	clinical testing	Invitae	Jan 17, 2024	- -

not specified

Benign:1

Benign, criteria provided, single submitter

clinical testing

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

Dec 24, 2019

Variant summary: BRAF c.1150A>G (p.Arg384Gly) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00018 in 251312 control chromosomes, exclusively reported within the East Asian subpopulation at a frequency of 0.0025, in the gnomAD database. The observed variant frequency within East Asian control individuals is approximately 1000-fold of the estimated maximal allele frequency expected for a pathogenic variant in BRAF causing Noonan Syndrome and Related Conditions phenotype (2.5e-06), strongly suggesting that the variant is a benign polymorphism. c.1150A>G has been reported in the literature in a fetus with abnormal ultrasound findings (suspected of Noonan Syndrome) and in individuals with various cancer phenotypes (Croonen_2013, Zhang_2015, Griffith_2018), however, without strong evidence for causality. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Two submitters, including an expert panel (ClinGen RASopathy Variant Curation Expert Panel), have provided clinical-significance assessments for this variant in ClinVar after 2014, and classified the variant as likely benign / benign (expert panel). Based on the evidence outlined above, the variant was classified as benign. -

Noonan syndrome and Noonan-related syndrome

Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Apr 29, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.21

BayesDel_addAF

Uncertain

0.018

BayesDel_noAF

Pathogenic

0.25

Cadd

Uncertain

Dann

Uncertain

1.0

Eigen

Benign

-0.032

Eigen_PC

Benign

0.14

FATHMM_MKL

Uncertain

0.87

LIST_S2

Uncertain

0.95

D;D;D;D

M_CAP

Benign

0.045

MetaRNN

Benign

0.024

T;T;T;T

MetaSVM

Benign

-0.55

MutationTaster

Benign

1.0

PrimateAI

Uncertain

0.73

Polyphen

0.19

.;.;B;.

Vest4

0.59

MutPred

0.45

Loss of stability (P = 0.0819);Loss of stability (P = 0.0819);Loss of stability (P = 0.0819);Loss of stability (P = 0.0819);

MVP

0.99

MPC

1.2

ClinPred

0.095

GERP RS

5.7

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.21

gMVP

0.61

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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