rs369635503

Positions:

• chr7-140778094-T-C

Variant summary

Our verdict is Benign. Variant got -11 ACMG points: 0P and 11B. BP5 BP7 BA1 BP4

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_004333.6 intron
• Clinical Significance: Benign reviewed by expert panel U:1 B:9
• Conservation: PhyloP100: 0.0160

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 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -11 ACMG points.

• BP4: For more information check the summary or visit ClinGen Evidence Repository.
• BP5: For more information check the summary or visit ClinGen Evidence Repository.
• BP7: For more information check the summary or visit ClinGen Evidence Repository.
• 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	c.1553-19A>G		intron_variant		ENST00000644969.2	NP_001361187.1
BRAF	NM_004333.6	c.1433-19A>G		intron_variant		ENST00000646891.2	NP_004324.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
BRAF	ENST00000644969.2	c.1553-19A>G		intron_variant			NM_001374258.1	ENSP00000496776.1
BRAF	ENST00000646891.2	c.1433-19A>G		intron_variant			NM_004333.6	ENSP00000493543.1

Frequencies

GnomAD3 genomes AF: 0.00110 AC: 168 AN: 152208 Hom.: 0 Cov.: 32

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.: 2 AF XY: 0.000988 AC XY: 134 AN XY: 135684

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.: 7 Cov.: 29 AF XY: 0.00203 AC XY: 1477 AN XY: 725958

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.: 0 Cov.: 32 AF XY: 0.000779 AC XY: 58 AN XY: 74486

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.: 1

Bravo AF: 0.00112

ClinVar

Significance: Benign

Submissions summary: Uncertain:1 Benign:9

Revision: reviewed by expert panel

Submissions by phenotype

not provided Uncertain:1 Benign:5

Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Oct 02, 2023	- -
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	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
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	-	- -

not specified Benign:2

Likely benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
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. -

RASopathy Benign:2

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 25, 2024	- -
Benign, reviewed by expert panel	curation	ClinGen RASopathy Variant Curation Expert Panel	Sep 17, 2024	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) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	10
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

Other links and lift over

dbSNP: rs369635503; hg19: chr7-140477894; COSMIC: COSV104607670; COSMIC: COSV104607670;