NM_001374258.1:c.2248-12_2248-5dupTTTTTTTT

Variant names:

• chr7-140734774-C-CAAAAAAAA
• rs373442098
• NM_001374258.1:c.2248-12_2248-5dupTTTTTTTT

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 0P and 0B.

The NM_001374258.1(BRAF):​c.2248-12_2248-5dupTTTTTTTT variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000168 in 773,804 control chromosomes in the GnomAD database, with no homozygous occurrence. There is a variant allele frequency bias in the population database for this variant (GnomAdExome4), which may indicate mosaicism or somatic mutations in the reference population data. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.000081 (0 hom., cov: 27)
  • Exomes 𝑓: 0.000015 (0 hom.)
• Consequence: BRAF NM_001374258.1 splice_region, intron
• Clinical Significance: Not reported in ClinVar
• 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: Uncertain_significance. The variant received 0 ACMG points.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
BRAF	NM_001374258.1	c.2248-12_2248-5dupTTTTTTTT		splice_region_variant, intron_variant	Intron 18 of 19	ENST00000644969.2	NP_001361187.1
BRAF	NM_004333.6	c.2128-12_2128-5dupTTTTTTTT		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.2248-5_2248-4insTTTTTTTT		splice_region_variant, intron_variant	Intron 18 of 19		NM_001374258.1	ENSP00000496776.1
BRAF	ENST00000646891.2	c.2128-5_2128-4insTTTTTTTT		splice_region_variant, intron_variant	Intron 17 of 17		NM_004333.6	ENSP00000493543.1

Frequencies

GnomAD3 genomes AF: 0.0000814 AC: 2 AN: 24574 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: 0.0000761

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.0000147 AC: 11 AN: 749228 Hom.: 0 Cov.: 28 AF XY: 0.0000239 AC XY: 9 AN XY: 377288

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

African (AFR) AF: 0.00 AC: 0 AN: 16174

American (AMR) AF: 0.00 AC: 0 AN: 15314

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 12782

East Asian (EAS) AF: 0.0000449 AC: 1 AN: 22254

South Asian (SAS) AF: 0.000111 AC: 4 AN: 36126

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 23690

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2692

European-Non Finnish (NFE) AF: 0.0000102 AC: 6 AN: 589290

Other (OTH) AF: 0.00 AC: 0 AN: 30906

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.0000000000113747), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.0000814 AC: 2 AN: 24576 Hom.: 0 Cov.: 27 AF XY: 0.0000868 AC XY: 1 AN XY: 11524

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

African (AFR) AF: 0.000185 AC: 1 AN: 5416

American (AMR) AF: 0.00 AC: 0 AN: 1856

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 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: 0.00 AC: 0 AN: 1160

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

European-Non Finnish (NFE) AF: 0.0000761 AC: 1 AN: 13144

Other (OTH) AF: 0.00 AC: 0 AN: 302

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		1.2

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs373442098; hg19: chr7-140434574;