rs1267621

Variant names:

• chr7-140856367-C-T
• rs1267621
• NM_001374258.1:c.139-6155G>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001374258.1(BRAF):​c.139-6155G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.205 in 151,908 control chromosomes in the GnomAD database, including 3,881 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.21 (3881 hom., cov: 31)
• Consequence: BRAF NM_001374258.1 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.69
• Publications: 10 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: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.98).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.342 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
BRAF	NM_001374258.1	c.139-6155G>A		intron_variant	Intron 1 of 19	ENST00000644969.2	NP_001361187.1
BRAF	NM_004333.6	c.139-6155G>A		intron_variant	Intron 1 of 17	ENST00000646891.2	NP_004324.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
BRAF	ENST00000644969.2	c.139-6155G>A		intron_variant	Intron 1 of 19		NM_001374258.1	ENSP00000496776.1
BRAF	ENST00000646891.2	c.139-6155G>A		intron_variant	Intron 1 of 17		NM_004333.6	ENSP00000493543.1

Frequencies

GnomAD3 genomes AF: 0.205 AC: 31159 AN: 151790 Hom.: 3862 Cov.: 31

Gnomad AFR AF: 0.346

Gnomad AMI AF: 0.104

Gnomad AMR AF: 0.145

Gnomad ASJ AF: 0.167

Gnomad EAS AF: 0.172

Gnomad SAS AF: 0.308

Gnomad FIN AF: 0.152

Gnomad MID AF: 0.261

Gnomad NFE AF: 0.140

Gnomad OTH AF: 0.194

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.205 AC: 31211 AN: 151908 Hom.: 3881 Cov.: 31 AF XY: 0.206 AC XY: 15330 AN XY: 74256

African (AFR) AF: 0.346 AC: 14351 AN: 41426

American (AMR) AF: 0.145 AC: 2207 AN: 15264

Ashkenazi Jewish (ASJ) AF: 0.167 AC: 578 AN: 3468

East Asian (EAS) AF: 0.173 AC: 894 AN: 5176

South Asian (SAS) AF: 0.308 AC: 1484 AN: 4822

European-Finnish (FIN) AF: 0.152 AC: 1595 AN: 10488

Middle Eastern (MID) AF: 0.264 AC: 77 AN: 292

European-Non Finnish (NFE) AF: 0.140 AC: 9521 AN: 67950

Other (OTH) AF: 0.194 AC: 409 AN: 2110

Alfa AF: 0.160 Hom.: 2854

Bravo AF: 0.206

Asia WGS AF: 0.249 AC: 867 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.98
CADD	Benign	0.15
DANN	Benign	0.37
PhyloP100		-1.7
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
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

Other links and lift over

dbSNP: rs1267621; hg19: chr7-140556167;