7-140734774-CAAAAAA-CAAAAA

Variant names:

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

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP6_Very_Strong BS1 BS2

The NM_001374258.1(BRAF):​c.2248-5delT variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0345 in 713,756 control chromosomes in the GnomAD database, including 16 homozygotes. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.012 (3 hom., cov: 27)
  • Exomes 𝑓: 0.035 (13 hom.)
• Consequence: BRAF NM_001374258.1 splice_region, intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:11
• 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 -16 ACMG points.

• BP6: Variant 7-140734774-CA-C is Benign according to our data. Variant chr7-140734774-CA-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 44821.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0118 (290/24564) while in subpopulation NFE AF = 0.0164 (215/13132). AF 95% confidence interval is 0.0146. There are 3 homozygotes in GnomAd4. There are 131 alleles in the male GnomAd4 subpopulation. Median coverage is 27. This position passed quality control check.
• BS2: High AC in GnomAd4 at 290 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
BRAF	NM_001374258.1	c.2248-5delT		splice_region_variant, intron_variant	Intron 18 of 19	ENST00000644969.2	NP_001361187.1
BRAF	NM_004333.6	c.2128-5delT		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.2248-5delT		splice_region_variant, intron_variant	Intron 18 of 19		NM_001374258.1	ENSP00000496776.1
BRAF	ENST00000646891.2	c.2128-5delT		splice_region_variant, intron_variant	Intron 17 of 17		NM_004333.6	ENSP00000493543.1

Frequencies

GnomAD3 genomes AF: 0.0118 AC: 291 AN: 24562 Hom.: 3 Cov.: 27

Gnomad AFR AF: 0.00741

Gnomad AMI AF: 0.0179

Gnomad AMR AF: 0.0130

Gnomad ASJ AF: 0.00137

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000862

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0165

Gnomad OTH AF: 0.0236

GnomAD4 exome AF: 0.0353 AC: 24361 AN: 689192 Hom.: 13 Cov.: 28 AF XY: 0.0349 AC XY: 12125 AN XY: 347002

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

African (AFR) AF: 0.0376 AC: 542 AN: 14416

American (AMR) AF: 0.0358 AC: 506 AN: 14124

Ashkenazi Jewish (ASJ) AF: 0.0343 AC: 406 AN: 11838

East Asian (EAS) AF: 0.0455 AC: 912 AN: 20036

South Asian (SAS) AF: 0.0314 AC: 1049 AN: 33388

European-Finnish (FIN) AF: 0.0398 AC: 875 AN: 21984

Middle Eastern (MID) AF: 0.0308 AC: 77 AN: 2500

European-Non Finnish (NFE) AF: 0.0348 AC: 18885 AN: 542644

Other (OTH) AF: 0.0392 AC: 1109 AN: 28262

⚠️ 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: 0.0118 AC: 290 AN: 24564 Hom.: 3 Cov.: 27 AF XY: 0.0114 AC XY: 131 AN XY: 11516

African (AFR) AF: 0.00738 AC: 40 AN: 5418

American (AMR) AF: 0.0129 AC: 24 AN: 1854

Ashkenazi Jewish (ASJ) AF: 0.00137 AC: 1 AN: 732

East Asian (EAS) AF: 0.00 AC: 0 AN: 908

South Asian (SAS) AF: 0.00 AC: 0 AN: 894

European-Finnish (FIN) AF: 0.000862 AC: 1 AN: 1160

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 52

European-Non Finnish (NFE) AF: 0.0164 AC: 215 AN: 13132

Other (OTH) AF: 0.0232 AC: 7 AN: 302

Alfa AF: 0.00 Hom.: 0

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:11

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:6

Jul 13, 2012

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Likely 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

- -

May 20, 2015

Eurofins Ntd Llc (ga)

Significance: 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

- -

-

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

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

May 10, 2023

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.2128-5delT 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 allele was found at a frequency of 0.012 in 24396 control chromosomes in the gnomAD database, including 3 homozygotes. The observed variant frequency is approximately 2527.18 fold of the estimated maximal expected allele frequency for a pathogenic variant in BRAF causing Cardiofaciocutaneous Syndrome phenotype (4.7e-06), strongly suggesting that the variant is benign. To our knowledge, no occurrence of c.2128-5delT in individuals affected with Cardiofaciocutaneous Syndrome and no experimental evidence demonstrating its impact on protein function have been reported. Four ClinVar submitters (evaluation after 2014) have cited the variant, and all laboratories classified the variant as benign (n = 2) or likely benign (n = 2). Based on the evidence outlined above, the variant was classified as benign. -

Noonan syndrome with multiple lentigines Benign:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Cardio-facio-cutaneous syndrome Benign:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Noonan syndrome Benign:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

RASopathy Benign:1

Feb 02, 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

Oct 01, 2019

Genome Diagnostics Laboratory, The Hospital for Sick Children

Significance: Likely 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		=98/2	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: COSV56304400;