chr7-140734774-C-CAAAAAAAAAAAAAAAAA

Position:

• chr7-140734774-C-CAAAAAAAAAAAAAAAAA

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_001374258.1(BRAF):​c.2248-5_2248-4insTTTTTTTTTTTTTTTTT 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 0.00000258 in 773,824 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.000041 (0 hom., cov: 27)
  • Exomes 𝑓: 0.0000013 (0 hom.)
• Consequence: BRAF NM_001374258.1 splice_region, splice_polypyrimidine_tract, intron
• Clinical Significance: Not reported in ClinVar
• 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 Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
BRAF	NM_001374258.1	c.2248-5_2248-4insTTTTTTTTTTTTTTTTT		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		ENST00000644969.2	NP_001361187.1
BRAF	NM_004333.6	c.2128-5_2128-4insTTTTTTTTTTTTTTTTT		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.2248-5_2248-4insTTTTTTTTTTTTTTTTT		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant			NM_001374258.1	ENSP00000496776
BRAF	ENST00000646891.2	c.2128-5_2128-4insTTTTTTTTTTTTTTTTT		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant			NM_004333.6	ENSP00000493543	P4

Frequencies

GnomAD3 genomes AF: 0.0000407 AC: 1 AN: 24572 Hom.: 0 Cov.: 27

Gnomad AFR AF: 0.000185

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000133 AC: 1 AN: 749252 Hom.: 0 Cov.: 28 AF XY: 0.00000265 AC XY: 1 AN XY: 377304

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000170

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.0000407 AC: 1 AN: 24572 Hom.: 0 Cov.: 27 AF XY: 0.00 AC XY: 0 AN XY: 11522

Gnomad4 AFR AF: 0.000185

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

ClinVar

Not reported in ClinVar

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;