rs371877084

chr7-140924626-C-Achr7-140924626-C-T

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 1P and 20B. PP2 BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001374258.1(BRAF):c.78G>T(p.Glu26Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00188 in 1,519,096 control chromosomes in the GnomAD database, including 50 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E26K) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.010 (30 hom., cov: 31)
  • Exomes 𝑓: 0.00098 (20 hom.)
• Consequence: BRAF NM_001374258.1 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:17 O:1
• Conservation: PhyloP100: 0.916

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]

ACMG classification

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=0.00439623).
• BP6: Variant 7-140924626-C-A is Benign according to our data. Variant chr7-140924626-C-A is described in ClinVar as [Likely_benign]. Clinvar id is 40337.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-140924626-C-A is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.01 (1516/150966) while in subpopulation AFR AF= 0.0351 (1445/41202). AF 95% confidence interval is 0.0336. There are 30 homozygotes in gnomad4. There are 711 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High AC in GnomAd at 1515 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
BRAF	NM_001374258.1	c.78G>T	p.Glu26Asp	missense_variant	1/20	ENST00000644969.2
BRAF	NM_004333.6	c.78G>T	p.Glu26Asp	missense_variant	1/18	ENST00000646891.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BRAF	ENST00000644969.2	c.78G>T	p.Glu26Asp	missense_variant	1/20		NM_001374258.1
BRAF	ENST00000646891.2	c.78G>T	p.Glu26Asp	missense_variant	1/18		NM_004333.6	P4

Frequencies

GnomAD3 genomes AF: 0.0100 AC: 1515 AN: 150862 Hom.: 30 Cov.: 31

Gnomad AFR AF: 0.0351

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00289

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00980

Gnomad NFE AF: 0.000163

Gnomad OTH AF: 0.00624

GnomAD3 exomes AF: 0.00235 AC: 296 AN: 125944 Hom.: 6 AF XY: 0.00168 AC XY: 116 AN XY: 69078

Gnomad AFR exome AF: 0.0409

Gnomad AMR exome AF: 0.00204

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000900

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000107

Gnomad OTH exome AF: 0.00102

GnomAD4 exome AF: 0.000985 AC: 1347 AN: 1368130 Hom.: 20 Cov.: 30 AF XY: 0.000820 AC XY: 554 AN XY: 675502

Gnomad4 AFR exome AF: 0.0343

Gnomad4 AMR exome AF: 0.00244

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000381

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000796

Gnomad4 OTH exome AF: 0.00191

GnomAD4 genome AF: 0.0100 AC: 1516 AN: 150966 Hom.: 30 Cov.: 31 AF XY: 0.00964 AC XY: 711 AN XY: 73790

Gnomad4 AFR AF: 0.0351

Gnomad4 AMR AF: 0.00289

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000163

Gnomad4 OTH AF: 0.00618

Alfa AF: 0.00522 Hom.: 1

Bravo AF: 0.0113

ESP6500AA AF: 0.0174 AC: 26

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000634 AC: 22

Asia WGS AF: 0.00173 AC: 6 AN: 3472

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:17 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:6 Other:1

not provided, no classification provided	reference population	ITMI	Sep 19, 2013	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Jun 05, 2018	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Apr 20, 2016	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 28, 2017	p.Glu26Asp in exon 1 of BRAF: This variant is not expected to have clinical sign ificance because it has been identified in 1.7% (26/1496) of African American ch romosomes from a large population study by the NHLBI Exome Sequencing Project (h ttp://evs.gs.washington.edu/EVS/; dbSNP rs371877084). -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -

not provided Benign:3

Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Oct 28, 2015	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Mar 02, 2023	- -

RASopathy Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 10, 2012	The variant is found in NOONAN panel(s). -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -

Noonan syndrome 7 Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

Cardiofaciocutaneous syndrome 1 Benign:1

Benign, criteria provided, single submitter

clinical testing

Center for Human Genetics, Inc, Center for Human Genetics, Inc

Nov 01, 2016

- -

Noonan syndrome Benign:1

Likely benign, no assertion criteria provided

clinical testing

Service de Génétique Moléculaire, Hôpital Robert Debré

-

- -

LEOPARD syndrome 3 Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Cardiovascular phenotype Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 20, 2019

This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Noonan syndrome and Noonan-related syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Mar 30, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.092
BayesDel_addAF	Benign	-0.33	T
BayesDel_noAF	Benign	-0.22
Cadd	Benign	20
Dann	Uncertain	0.98
Eigen	Benign	-0.40
Eigen_PC	Benign	-0.28
FATHMM_MKL	Benign	0.39	N
LIST_S2	Benign	0.80	T;T;T;T;T
MetaRNN	Benign	0.0044	T;T;T;T;T
MetaSVM	Benign	-0.88	T
MutationTaster	Benign	0.88	N
PrimateAI	Pathogenic	0.92	D
Polyphen		0.37	.;.;B;.;.
Vest4		0.32
MutPred		0.16		Loss of helix (P = 0.0093);Loss of helix (P = 0.0093);Loss of helix (P = 0.0093);Loss of helix (P = 0.0093);Loss of helix (P = 0.0093);
MVP		0.58
MPC		0.86
ClinPred		0.040	T
GERP RS		2.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.077
gMVP		0.17

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: rs371877084; hg19: chr7-140624426; COSMIC: COSV56062586;