7-140734774-C-CAA

Variant names:

• chr7-140734774-C-CAA
• rs373442098
• NM_001374258.1:c.2248-6_2248-5dupTT

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP6_Moderate

The NM_001374258.1(BRAF):​c.2248-6_2248-5dupTT variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00153 in 769,240 control chromosomes in the GnomAD database, with no homozygous occurrence. There is a variant allele frequency bias in the population database for this variant (GnomAd4), which may indicate mosaicism or somatic mutations in the reference population data. 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, intron
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• 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: Likely_benign. The variant received -2 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 VariationId is 477687.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

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

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

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

African (AFR) AF: 0.000620 AC: 10 AN: 16124

American (AMR) AF: 0.00151 AC: 23 AN: 15216

Ashkenazi Jewish (ASJ) AF: 0.00197 AC: 25 AN: 12700

East Asian (EAS) AF: 0.00181 AC: 40 AN: 22138

South Asian (SAS) AF: 0.00512 AC: 183 AN: 35756

European-Finnish (FIN) AF: 0.00170 AC: 40 AN: 23534

Middle Eastern (MID) AF: 0.000747 AC: 2 AN: 2678

European-Non Finnish (NFE) AF: 0.00137 AC: 801 AN: 585800

Other (OTH) AF: 0.00146 AC: 45 AN: 30722

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

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

⚠️ 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: 0.00162 AC: 3 AN: 1856

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 732

East Asian (EAS) AF: 0.00110 AC: 1 AN: 908

South Asian (SAS) AF: 0.00112 AC: 1 AN: 892

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: 0.000152 AC: 2 AN: 13142

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 = 0.000740941), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.00 Hom.: 0

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

RASopathy Benign:1

Dec 15, 2021

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		1.2
Mutation Taster		=100/0	polymorphism

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;