chr7-140800366-T-C

Position:

chr7-140800366-T-C

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.1772A>G (p.Asn591Ser) variant in the SOS1 gene is 0.054% (11/11524) of Latino 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) LINK:https://erepo.genome.network/evrepo/ui/classification/CA4516861/MONDO:0021060/004

Frequency

Genomes: 𝑓 0.000026 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000099 ( 0 hom. )

Consequence

BRAF
NM_004333.6 missense

Scores

Clinical Significance

Benign reviewed by expert panel B:3

Conservation

PhyloP100: -0.00500

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:

BRAF (HGNC:):

BRAF links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -8 ACMG points.

BA1

For more information check the summary or visit ClinGen Evidence Repository.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
BRAF	NM_001374258.1 linkuse as main transcript	c.976A>G	p.Ile326Val	missense_variant	7/20	ENST00000644969.2	NP_001361187.1
BRAF	NM_004333.6 linkuse as main transcript	c.976A>G	p.Ile326Val	missense_variant	7/18	ENST00000646891.2	NP_004324.2	P15056

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
BRAF	ENST00000644969.2 linkuse as main transcript	c.976A>G	p.Ile326Val	missense_variant	7/20		NM_001374258.1	ENSP00000496776.1		A0A2R8Y8E0
BRAF	ENST00000646891.2 linkuse as main transcript	c.976A>G	p.Ile326Val	missense_variant	7/18		NM_004333.6	ENSP00000493543.1		P15056

Frequencies

GnomAD3 genomes

AF:

0.0000263

AC:

AN:

152074

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:

0.000578

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.0000945

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000795

AC:

AN:

251450

Hom.:

AF XY:

0.0000883

AC XY:

AN XY:

135898

show subpopulations

Gnomad AFR exome

AF:

0.0000615

Gnomad AMR exome

AF:

0.0000578

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000761

Gnomad SAS exome

AF:

0.0000980

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000985

AC:

144

AN:

1461786

Hom.:

Cov.:

AF XY:

0.0000990

AC XY:

AN XY:

727186

show subpopulations

Gnomad4 AFR exome

AF:

0.0000597

Gnomad4 AMR exome

AF:

0.0000447

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00338

Gnomad4 SAS exome

AF:

0.0000348

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

8.99e-7

Gnomad4 OTH exome

AF:

0.0000331

GnomAD4 genome

AF:

0.0000263

AC:

AN:

152074

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74262

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000578

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.0000945

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.00000756

ExAC

AF:

0.0000906

AC:

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

RASopathy

Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 18, 2023	- -
Benign, reviewed by expert panel	curation	ClinGen RASopathy Variant Curation Expert Panel	Apr 18, 2017	The filtering allele frequency of the c.1772A>G (p.Asn591Ser) variant in the SOS1 gene is 0.054% (11/11524) of Latino 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) -

not provided

Benign:1

Benign, criteria provided, single submitter

clinical testing

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

Mar 12, 2017

Variant summary: The c.976A>G (p.Ile326Val) in BRAF gene is a missense change that involves a non-conserved nucleotide and 5/5 in silico tools predict benign outcome. The variant is located outside of any known functional domain and behaved like wildtype in phosphorylation assay (Razzaque_2007). The variant is present in the large control population datasets of ExAC and gnomAD at a frequency 0.00009 and 0.000075, respectively (11/ 121408 and 21/ 277182 chrs tested, respectively), predominantly in individuals of East Asian descent ( allele frequency: 0.00104 and 0.0007, respectively). These frequencies exceed the maximal estimated expected frequency of a pathogenic allele (0.0000025) in this gene. The variant was identified in one patient with Noonan syndrome who also carried a de novo mutation in BRAF gene, p. E501K, a known pathogenic variant associated with CFC. Taking together, the variant was classified as Benign. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.057

BayesDel_addAF

Benign

-0.50

BayesDel_noAF

Benign

-0.57

CADD

Benign

0.077

DANN

Benign

0.30

DEOGEN2

Benign

0.27

.;.;T;.

Eigen

Benign

-1.8

Eigen_PC

Benign

-1.8

FATHMM_MKL

Benign

0.15

LIST_S2

Benign

0.079

T;T;T;T

M_CAP

Benign

0.017

MetaRNN

Benign

0.0084

T;T;T;T

MetaSVM

Benign

-0.97

MutationAssessor

Benign

0.0

.;.;N;.

PrimateAI

Benign

0.23

PROVEAN

Benign

0.15

.;.;.;N

REVEL

Benign

0.16

Sift

Benign

0.69

.;.;.;T

Sift4G

Benign

0.91

.;.;.;T

Polyphen

0.0

.;.;B;.

Vest4

0.14

MutPred

0.14

Loss of catalytic residue at P328 (P = 0.0271);Loss of catalytic residue at P328 (P = 0.0271);Loss of catalytic residue at P328 (P = 0.0271);Loss of catalytic residue at P328 (P = 0.0271);

MVP

0.36

MPC

0.79

ClinPred

0.011

GERP RS

-5.3

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.014

gMVP

0.17

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.040

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