rs397516907

Positions:

chr7-140800374-G-A

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BA1

This summary comes from the ClinGen Evidence Repository: The filtering allele frequency of the c.968C>T (p.Ser323Leu) variant in the BRAF gene is 0.06% for South Asian chromosomes by the Exome Aggregation Consortium (17/16512 with 95% CI), which is a high enough frequency to be classified as benign based on thresholds defined by the ClinGen RASopathy Expert panel for autosomal dominant RASopathy variants (BA1). LINK:https://erepo.genome.network/evrepo/ui/classification/CA135149/MONDO:0021060/004

Frequency

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

Exomes 𝑓: 0.000075 ( 0 hom. )

Consequence

BRAF
NM_001374258.1 missense

Scores

Clinical Significance

Benign reviewed by expert panel U:1B:5

Conservation

PhyloP100: 9.21

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 -8 ACMG points.

BA1

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
BRAF	NM_001374258.1 linkuse as main transcript	c.968C>T	p.Ser323Leu	missense_variant	7/20	ENST00000644969.2
BRAF	NM_004333.6 linkuse as main transcript	c.968C>T	p.Ser323Leu	missense_variant	7/18	ENST00000646891.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BRAF	ENST00000644969.2 linkuse as main transcript	c.968C>T	p.Ser323Leu	missense_variant	7/20		NM_001374258.1
BRAF	ENST00000646891.2 linkuse as main transcript	c.968C>T	p.Ser323Leu	missense_variant	7/18		NM_004333.6	P4

Frequencies

GnomAD3 genomes

AF:

0.0000131

AC:

AN:

152158

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:

0.00

Gnomad SAS

AF:

0.000415

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000123

AC:

AN:

251464

Hom.:

AF XY:

0.000140

AC XY:

AN XY:

135900

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000980

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000879

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000752

AC:

110

AN:

1461834

Hom.:

Cov.:

AF XY:

0.0000963

AC XY:

AN XY:

727216

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.00115

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000450

Gnomad4 OTH exome

AF:

0.0000662

GnomAD4 genome

AF:

0.0000131

AC:

AN:

152276

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74454

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000415

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000564

Hom.:

Bravo

AF:

0.0000113

ExAC

AF:

0.000157

AC:

ClinVar

Significance: Benign

Submissions summary: Uncertain:1Benign:5

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

RASopathy

Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Aug 05, 2023	- -
Benign, reviewed by expert panel	curation	ClinGen RASopathy Variant Curation Expert Panel	Apr 03, 2017	The filtering allele frequency of the c.968C>T (p.Ser323Leu) variant in the BRAF gene is 0.06% for South Asian chromosomes by the Exome Aggregation Consortium (17/16512 with 95% CI), which is a high enough frequency to be classified as benign based on thresholds defined by the ClinGen RASopathy Expert panel for autosomal dominant RASopathy variants (BA1). -

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Apr 18, 2012

Variant classified as Uncertain Significance - Favor Benign. The Ser323Leu varia nt has not been reported in the literature nor previously identified by our labo ratory. Serine (Ser) at this position is conserved across mammals but not into lower species and computational analyses (biochemical amino acid properties, Pol yPhen2, SIFT, AlignGVGD) do not provide strong support for or against pathogenic ity. In the absence of additional information, the clinical significance of thi s variant cannot be determined at this time. -

BRAF-related disorder

Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jul 05, 2021

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

not provided

Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Feb 28, 2019

- -

Noonan syndrome and Noonan-related syndrome

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Aug 20, 2020

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.069

BayesDel_addAF

Benign

-0.22

BayesDel_noAF

Benign

-0.15

CADD

Pathogenic

DANN

Uncertain

0.98

Eigen

Uncertain

0.30

Eigen_PC

Uncertain

0.41

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.95

D;D;D;D

M_CAP

Benign

0.036

MetaRNN

Benign

0.10

T;T;T;T

MetaSVM

Benign

-0.56

MutationTaster

Benign

1.0

PrimateAI

Uncertain

0.56

Polyphen

0.76

.;.;P;.

Vest4

0.68

MutPred

0.22

Loss of phosphorylation at S323 (P = 0.0063);Loss of phosphorylation at S323 (P = 0.0063);Loss of phosphorylation at S323 (P = 0.0063);Loss of phosphorylation at S323 (P = 0.0063);

MVP

0.71

MPC

0.92

ClinPred

0.15

GERP RS

6.1

Varity_R

0.061

gMVP

0.55

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