7-140734774-CAAAAAA-CAAAAAAA

Variant names:

• chr7-140734774-C-CA
• rs373442098
• NM_001374258.1:c.2248-5dupT

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP6 BA1

The NM_001374258.1(BRAF):​c.2248-5dupT variant causes a splice region, 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, intron
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4 B:9 O:1
• Conservation: PhyloP100: 1.19
• Publications: 3 publications found

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 Gene-Disease associations (from GenCC):

• cardiofaciocutaneous syndrome

  Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: ClinGen, Orphanet
• cardiofaciocutaneous syndrome 1

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), PanelApp Australia, Ambry Genetics, G2P, Genomics England PanelApp
• LEOPARD syndrome 3

  Inheritance: AD Classification: DEFINITIVE, STRONG, LIMITED Submitted by: G2P, Labcorp Genetics (formerly Invitae), Ambry Genetics, Genomics England PanelApp
• Noonan syndrome 7

  Inheritance: AD Classification: DEFINITIVE, STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), PanelApp Australia, G2P, Ambry Genetics, Genomics England PanelApp
• Noonan syndrome

  Inheritance: AD Classification: MODERATE Submitted by: ClinGen
• Noonan syndrome with multiple lentigines

  Inheritance: AD Classification: SUPPORTIVE, LIMITED Submitted by: ClinGen, Orphanet
• anaplastic astrocytoma

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics
• Costello syndrome

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

ACMG classification

Our verdict: Benign. The variant received -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 VariationId is 44820.
• 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 rank	MANE	Protein	UniProt
BRAF	NM_001374258.1	c.2248-5dupT		splice_region_variant, intron_variant	Intron 18 of 19	ENST00000644969.2	NP_001361187.1
BRAF	NM_004333.6	c.2128-5dupT		splice_region_variant, intron_variant	Intron 17 of 17	ENST00000646891.2	NP_004324.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
BRAF	ENST00000644969.2	c.2248-5_2248-4insT		splice_region_variant, intron_variant	Intron 18 of 19		NM_001374258.1	ENSP00000496776.1
BRAF	ENST00000646891.2	c.2128-5_2128-4insT		splice_region_variant, intron_variant	Intron 17 of 17		NM_004333.6	ENSP00000493543.1

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

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.0631 AC: 937 AN: 14852

American (AMR) AF: 0.0962 AC: 1357 AN: 14112

Ashkenazi Jewish (ASJ) AF: 0.149 AC: 1679 AN: 11272

East Asian (EAS) AF: 0.146 AC: 2846 AN: 19492

South Asian (SAS) AF: 0.163 AC: 5238 AN: 32058

European-Finnish (FIN) AF: 0.152 AC: 3269 AN: 21496

Middle Eastern (MID) AF: 0.135 AC: 324 AN: 2394

European-Non Finnish (NFE) AF: 0.149 AC: 75702 AN: 509494

Other (OTH) AF: 0.152 AC: 4111 AN: 27072

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

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

African (AFR) AF: 0.117 AC: 629 AN: 5360

American (AMR) AF: 0.214 AC: 393 AN: 1834

Ashkenazi Jewish (ASJ) AF: 0.301 AC: 215 AN: 714

East Asian (EAS) AF: 0.253 AC: 225 AN: 890

South Asian (SAS) AF: 0.265 AC: 234 AN: 882

European-Finnish (FIN) AF: 0.198 AC: 227 AN: 1146

Middle Eastern (MID) AF: 0.385 AC: 20 AN: 52

European-Non Finnish (NFE) AF: 0.303 AC: 3887 AN: 12818

Other (OTH) AF: 0.216 AC: 64 AN: 296

Alfa AF: 0.00 Hom.: 0

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:4 Benign:9 Other:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not specified Benign:5 Other:1

Sep 05, 2014

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 13, 2014

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: not provided

Review Status: no classification provided

Collection Method: clinical testing

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. -

Jun 26, 2015

Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 16, 2025

Laboratory of Genetics, Children's Clinical University Hospital Latvia

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Clinical Genetics, Academic Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Oct 10, 2019

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

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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 Benign:2

-

Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Noonan syndrome with multiple lentigines Uncertain:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Cardio-facio-cutaneous syndrome Uncertain:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Congenital long QT syndrome Uncertain:1

-

Genetics and Genomics Program, Sidra Medicine

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: research

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

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

RASopathy Benign:1

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Noonan syndrome and Noonan-related syndrome Benign:1

Jul 08, 2021

Genome Diagnostics Laboratory, The Hospital for Sick Children

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		1.2
Mutation Taster		=100/0	polymorphism

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

Other links and lift over

dbSNP: rs373442098; hg19: chr7-140434574; COSMIC: COSV56184569;