7-140734774-CAAAAAA-CAAAAAAAA

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP6_Moderate BS1 BS2

The NM_001374258.1(BRAF):c.2248-5_2248-4insTT 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 0.00153 in 769,240 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.00033 (0 hom., cov: 27)
  • Exomes 𝑓: 0.0016 (0 hom.)
• Consequence: BRAF NM_001374258.1 splice_region, splice_polypyrimidine_tract, intron
• Clinical Significance: Likely benign criteria provided, single submitter B: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 -10 ACMG points.

• BP6: Variant 7-140734774-C-CAA is Benign according to our data. Variant chr7-140734774-C-CAA is described in ClinVar as [Likely_benign]. Clinvar id is 477687.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.000326 (8/24572) while in subpopulation AMR AF= 0.00162 (3/1856). AF 95% confidence interval is 0.00044. There are 0 homozygotes in gnomad4. There are 4 alleles in male gnomad4 subpopulation. Median coverage is 27. This position pass quality control queck.
• BS2: High AC in GnomAd at 8 AD gene.

Transcripts

RefSeq

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

Frequencies

GnomAD3 genomes AF: 0.000326 AC: 8 AN: 24570 Hom.: 0 Cov.: 27

Gnomad AFR AF: 0.000185

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00162

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00108

Gnomad SAS AF: 0.00111

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000152

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00157 AC: 1169 AN: 744668 Hom.: 0 Cov.: 28 AF XY: 0.00165 AC XY: 619 AN XY: 374936

Gnomad4 AFR exome AF: 0.000620

Gnomad4 AMR exome AF: 0.00151

Gnomad4 ASJ exome AF: 0.00197

Gnomad4 EAS exome AF: 0.00181

Gnomad4 SAS exome AF: 0.00512

Gnomad4 FIN exome AF: 0.00170

Gnomad4 NFE exome AF: 0.00137

Gnomad4 OTH exome AF: 0.00146

GnomAD4 genome AF: 0.000326 AC: 8 AN: 24572 Hom.: 0 Cov.: 27 AF XY: 0.000347 AC XY: 4 AN XY: 11522

Gnomad4 AFR AF: 0.000185

Gnomad4 AMR AF: 0.00162

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00110

Gnomad4 SAS AF: 0.00112

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000152

Gnomad4 OTH AF: 0.00

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

RASopathy Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Dec 15, 2021

- -

Computational scores

Source: dbNSFP v4.3

Splicing

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;