7-140734774-CAAAAAA-CAAAAA

Position:

• chr7-140734774-CAAAAAA-CAAAAA

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP6_Very_Strong BS1 BS2

The NM_001374258.1(BRAF):​c.2248-5del 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 0.0345 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, splice_polypyrimidine_tract, intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:10
• 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 -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 [Likely_benign]. Clinvar id is 44821.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-140734774-CA-C is described in Lovd as [Likely_benign]. Variant chr7-140734774-CA-C is described in Lovd as [Benign]. Variant chr7-140734774-CA-C is described in Lovd as [Benign]. Variant chr7-140734774-CA-C is described in Lovd as [Likely_benign].
• 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 male gnomad4 subpopulation. Median coverage is 27. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 290 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
BRAF	NM_001374258.1	c.2248-5del		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		ENST00000644969.2	NP_001361187.1
BRAF	NM_004333.6	c.2128-5del		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.2248-5del		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant			NM_001374258.1	ENSP00000496776
BRAF	ENST00000646891.2	c.2128-5del		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant			NM_004333.6	ENSP00000493543	P4

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

Gnomad4 AFR exome AF: 0.0376

Gnomad4 AMR exome AF: 0.0358

Gnomad4 ASJ exome AF: 0.0343

Gnomad4 EAS exome AF: 0.0455

Gnomad4 SAS exome AF: 0.0314

Gnomad4 FIN exome AF: 0.0398

Gnomad4 NFE exome AF: 0.0348

Gnomad4 OTH exome AF: 0.0392

GnomAD4 genome AF: 0.0118 AC: 290 AN: 24564 Hom.: 3 Cov.: 27 AF XY: 0.0114 AC XY: 131 AN XY: 11516

Gnomad4 AFR AF: 0.00738

Gnomad4 AMR AF: 0.0129

Gnomad4 ASJ AF: 0.00137

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000862

Gnomad4 NFE AF: 0.0164

Gnomad4 OTH AF: 0.0232

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:5

Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	May 20, 2015	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Jul 13, 2012	- -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	May 10, 2023	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

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Cardio-facio-cutaneous syndrome Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Noonan syndrome Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

RASopathy Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Feb 01, 2024

- -

Noonan syndrome and Noonan-related syndrome Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Oct 01, 2019

- -

Computational scores

Source: dbNSFP v4.3

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

Publications

LitVar

Other links and lift over

dbSNP: rs373442098; hg19: chr7-140434574;