chr7-140734774-C-CA

Position:

• chr7-140734774-C-CA

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP6 BA1

The NM_001374258.1(BRAF):​c.2248-5_2248-4insT variant causes a splice region, splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.15 in 676,340 control chromosomes in the GnomAD database, including 424 homozygotes. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.25 (194 hom., cov: 27)
  • Exomes 𝑓: 0.15 (230 hom.)
• Consequence: BRAF NM_001374258.1 splice_region, splice_polypyrimidine_tract, intron
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4 B:8 O:1
• Conservation: PhyloP100: 1.19

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 -9 ACMG points.

• BP6: Variant 7-140734774-C-CA is Benign according to our data. Variant chr7-140734774-C-CA is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 44820.We mark this variant Likely_benign, oryginal submissions are: {Benign=5, not_provided=1, Uncertain_significance=3}.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.295 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
BRAF	NM_001374258.1	c.2248-5_2248-4insT		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		ENST00000644969.2	NP_001361187.1
BRAF	NM_004333.6	c.2128-5_2128-4insT		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		ENST00000646891.2	NP_004324.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
BRAF	ENST00000644969.2	c.2248-5_2248-4insT		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant			NM_001374258.1	ENSP00000496776
BRAF	ENST00000646891.2	c.2128-5_2128-4insT		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant			NM_004333.6	ENSP00000493543	P4

Frequencies

GnomAD3 genomes AF: 0.246 AC: 5920 AN: 24098 Hom.: 193 Cov.: 27

Gnomad AFR AF: 0.118

Gnomad AMI AF: 0.198

Gnomad AMR AF: 0.215

Gnomad ASJ AF: 0.301

Gnomad EAS AF: 0.250

Gnomad SAS AF: 0.265

Gnomad FIN AF: 0.198

Gnomad MID AF: 0.370

Gnomad NFE AF: 0.303

Gnomad OTH AF: 0.224

GnomAD4 exome AF: 0.146 AC: 95463 AN: 652242 Hom.: 230 Cov.: 28 AF XY: 0.146 AC XY: 47957 AN XY: 328656

Gnomad4 AFR exome AF: 0.0631

Gnomad4 AMR exome AF: 0.0962

Gnomad4 ASJ exome AF: 0.149

Gnomad4 EAS exome AF: 0.146

Gnomad4 SAS exome AF: 0.163

Gnomad4 FIN exome AF: 0.152

Gnomad4 NFE exome AF: 0.149

Gnomad4 OTH exome AF: 0.152

GnomAD4 genome AF: 0.245 AC: 5915 AN: 24098 Hom.: 194 Cov.: 27 AF XY: 0.238 AC XY: 2684 AN XY: 11266

Gnomad4 AFR AF: 0.117

Gnomad4 AMR AF: 0.214

Gnomad4 ASJ AF: 0.301

Gnomad4 EAS AF: 0.253

Gnomad4 SAS AF: 0.265

Gnomad4 FIN AF: 0.198

Gnomad4 NFE AF: 0.303

Gnomad4 OTH AF: 0.216

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:4 Benign:8 Other:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not specified Benign:4 Other:1

Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Oct 10, 2019	Variant summary: BRAF c.2128-5dupT alters a non-conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. 4/4 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant was absent in 151920 control chromosomes. However, multiple benign variants have been found in this polyT region. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation (2x benign, 1x VUS). Based on the evidence outlined above, the variant was classified as benign. -
not provided, no classification provided	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 13, 2014	2128-5_2128-4insT in intron 17 of BRAF: This variant is not expected to have clinical significance because it shifts but does not alter the splice consensus sequence. -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Sep 05, 2014	- -
Benign, criteria provided, single submitter	clinical testing	Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia	Jun 26, 2015	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -

not provided Benign:2

Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -

Noonan syndrome with multiple lentigines Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Cardio-facio-cutaneous syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Congenital long QT syndrome Uncertain:1

Uncertain significance, no assertion criteria provided

research

Genetics and Genomics Program, Sidra Medicine

-

The c.2128-5dupT variant in BRAF affects the splice region and is not reported in population databases like gnomAD, indicating rarity. However, there is currently insufficient evidence regarding its impact on splicing or its clinical significance. Due to the lack of supporting data, this variant is classified as a VUS. -

Noonan syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Noonan syndrome and Noonan-related syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Jul 08, 2021

- -

RASopathy Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Feb 01, 2024

- -

Computational scores

Source: dbNSFP v4.3

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: rs373442098; hg19: chr7-140434574;