rs369635503

Positions:

chr7-140778094-T-C

Variant summary

Our verdict is Benign. Variant got -11 ACMG points: 0P and 11B. BA1BP4BP5BP7

This summary comes from the ClinGen Evidence Repository: The c.1433-19A>G in BRAF is an intronic variant located in intron 11. The minor allele frequency of this variant in gnomAD v4 is 0.2572% (3030/1178128) in the European (non-Finnish) population, 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). This variant is not predicted by SpliceAI to impact splicing. In addition, it occurs at a nucleotide that is not conserved (BP4, BP7). This variant has been identified in at least 2 patients with clinical features of a RASopathy (PS4_Supporting not met; GeneDx, Greenwood Genetics, Otto von Guericke University Magdeburg, internal data, GTR ID's: 26957, 1019; ClinVar SCV000207632.1, SCV000167210.14). However, this variant has been identified in a patient with an alternate molecular basis for disease (BP5; GeneDx internal data, GTR ID's: 26957; ClinVar SCV000167210.14). In summary, this variant meets criteria to be classified as benign for autosomal dominant RASopathies based on the ACMG/AMP criteria applied, as specified by the ClinGen RASopathy Variant Curation Expert Panel: BA1, BP4, BP5, BP7 (Specification Version 2.1, 9/17/2024) LINK:https://erepo.genome.network/evrepo/ui/classification/CA232434/MONDO:0021060/049

Frequency

Genomes: 𝑓 0.0011 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0021 ( 7 hom. )

Consequence

BRAF
NM_001374258.1 intron

Scores

Clinical Significance

Benign reviewed by expert panel U:1B:8

Conservation

PhyloP100: 0.0160

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 -11 ACMG points.

BP4

BP5

BP7

BA1

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
BRAF	NM_001374258.1 linkuse as main transcript	c.1553-19A>G		intron_variant		ENST00000644969.2
BRAF	NM_004333.6 linkuse as main transcript	c.1433-19A>G		intron_variant		ENST00000646891.2

Ensembl

Gene	Transcript	HGVSc	Effect	MANE	Appris
BRAF	ENST00000644969.2 linkuse as main transcript	c.1553-19A>G	intron_variant	NM_001374258.1
BRAF	ENST00000646891.2 linkuse as main transcript	c.1433-19A>G	intron_variant	NM_004333.6	P4
	ENST00000700122.1 linkuse as main transcript	n.502+3226T>C	intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes

AF:

0.00110

AC:

168

AN:

152208

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000410

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000131

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:

0.00216

Gnomad OTH

AF:

0.000478

GnomAD3 exomes

AF:

0.000984

AC:

247

AN:

251054

Hom.:

AF XY:

0.000988

AC XY:

134

AN XY:

135684

show subpopulations

Gnomad AFR exome

AF:

0.000308

Gnomad AMR exome

AF:

0.0000580

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000185

Gnomad NFE exome

AF:

0.00203

Gnomad OTH exome

AF:

0.000817

GnomAD4 exome

AF:

0.00208

AC:

3040

AN:

1459080

Hom.:

Cov.:

AF XY:

0.00203

AC XY:

1477

AN XY:

725958

show subpopulations

Gnomad4 AFR exome

AF:

0.000240

Gnomad4 AMR exome

AF:

0.000157

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.000469

Gnomad4 NFE exome

AF:

0.00260

Gnomad4 OTH exome

AF:

0.00194

GnomAD4 genome

AF:

0.00110

AC:

168

AN:

152326

Hom.:

Cov.:

AF XY:

0.000779

AC XY:

AN XY:

74486

show subpopulations

Gnomad4 AFR

AF:

0.000409

Gnomad4 AMR

AF:

0.000131

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000207

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00216

Gnomad4 OTH

AF:

0.000473

Alfa

AF:

0.00158

Hom.:

Bravo

AF:

0.00112

ClinVar

Significance: Benign

Submissions summary: Uncertain:1Benign:8

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

not provided

Uncertain:1Benign:4

Uncertain significance, no assertion criteria provided	clinical testing	Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center	Jan 15, 2015	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	May 31, 2016	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Likely 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	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Oct 02, 2023	- -

not specified

Benign:2

Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Mar 23, 2020	Variant summary: BRAF c.1433-19A>G alters a nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. Several computational tools predict a significant impact on normal splicing: Four predict the variant no significant impact on splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 0.00098 in 251054 control chromosomes, predominantly at a frequency of 0.002 within the Non-Finnish European subpopulation in the gnomAD database, including 2 homozygotes. The observed variant frequency within Non-Finnish European control individuals in the gnomAD database is significantly higher than the estimated maximal expected allele frequency 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 found primarily in populations of Non-Finnish European origin. To our knowledge, no occurrence of c.1433-19A>G in individuals affected with Noonan Syndrome and Related Conditions and no experimental evidence demonstrating its impact on protein function have been reported. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation, two classified as likely benign/benign while one classified as VUS. Based on the evidence outlined above, the variant was classified as benign. -
Likely benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

RASopathy

Benign:2

Benign, reviewed by expert panel	curation	ClinGen RASopathy Variant Curation Expert Panel	Apr 03, 2017	The c.1433-19A>G variant in BRAF has been identified in at least 2 patients with clinical features of a RASopathy (PS4_Supporting; GeneDx, Greenwood Genetics, Otto von Guericke University Magdeburg, internal data, GTR ID's: 26957, 1019; ClinVar SCV000207632.1, SCV000167210.14). However, the filtering allele frequency of the c.1433-19A>G variant in the BRAF gene is 0.11% for European (Non-Finnish) chromosomes by the Exome Aggregation Consortium (120/65832 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). This variant has been identified in a patient with an alternate molecular basis for disease (BP5; GeneDx internal data, GTR ID's: 26957; ClinVar SCV000167210.14). This variant is a synonymous (silent) variant at a nucleotide that is not highly conserved and is not predicted to impact splicing (BP7). In summary, this variant meets criteria to be classified as benign. RASopathy-specific ACMG/AMP criteria applied (PMID:29493581): PS4_Supporting, BA1, BP5, BP7. -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 25, 2024	- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.82

CADD

Benign

DANN

Benign

0.69

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