rs956143558

chr7-140734774-C-A

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BP6_Very_Strong

The NM_001374258.1(BRAF):c.2248-4G>T variant causes a splice region, splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. 2/2 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.016 (0 hom., cov: 0)
  • Exomes 𝑓: 0.021 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: BRAF NM_001374258.1 splice_region, splice_polypyrimidine_tract, intron
• Scores: Splicing: ADA: 0.00007941
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 0.942

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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.51).
• BP6: Variant 7-140734774-C-A is Benign according to our data. Variant chr7-140734774-C-A is described in ClinVar as [Likely_benign]. Clinvar id is 377569.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-140734774-C-A is described in Lovd as [Likely_benign].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
BRAF	NM_001374258.1	c.2248-4G>T		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		ENST00000644969.2
BRAF	NM_004333.6	c.2128-4G>T		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		ENST00000646891.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BRAF	ENST00000644969.2	c.2248-4G>T		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant			NM_001374258.1
BRAF	ENST00000646891.2	c.2128-4G>T		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant			NM_004333.6	P4

Frequencies

GnomAD3 genomes AF: 0.00 AC: 398 AN: 24332 Hom.: 0 Cov.: 0 FAILED QC

Gnomad AFR AF: 0.0303

Gnomad AMI AF: 0.0364

Gnomad AMR AF: 0.0114

Gnomad ASJ AF: 0.00824

Gnomad EAS AF: 0.00764

Gnomad SAS AF: 0.0167

Gnomad FIN AF: 0.00345

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0133

Gnomad OTH AF: 0.0238

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.0205 AC: 15076 AN: 733840 Hom.: 0 Cov.: 23 AF XY: 0.0191 AC XY: 7061 AN XY: 369880

Gnomad4 AFR exome AF: 0.0146

Gnomad4 AMR exome AF: 0.00374

Gnomad4 ASJ exome AF: 0.00899

Gnomad4 EAS exome AF: 0.00612

Gnomad4 SAS exome AF: 0.0113

Gnomad4 FIN exome AF: 0.00547

Gnomad4 NFE exome AF: 0.0234

Gnomad4 OTH exome AF: 0.0164

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.0164 AC: 398 AN: 24336 Hom.: 0 Cov.: 0 AF XY: 0.0165 AC XY: 189 AN XY: 11428

Gnomad4 AFR AF: 0.0303

Gnomad4 AMR AF: 0.0109

Gnomad4 ASJ AF: 0.00824

Gnomad4 EAS AF: 0.00776

Gnomad4 SAS AF: 0.0169

Gnomad4 FIN AF: 0.00345

Gnomad4 NFE AF: 0.0133

Gnomad4 OTH AF: 0.0233

Alfa AF: 0.00978 Hom.: 0

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Jul 03, 2018	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Sep 14, 2015	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. -

Noonan syndrome and Noonan-related syndrome Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Dec 12, 2016

- -

RASopathy Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Jul 17, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.51
Cadd	Benign	7.2
Dann	Benign	0.53

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000079
dbscSNV1_RF	Benign	0.0060
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: rs956143558; hg19: chr7-140434574;