chr7-140755173-G-T

Variant names:

• chr7-140755173-G-T
• rs7801086
• NM_001374258.1:c.1815-940C>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.1815-940C>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.298 in 152,030 control chromosomes in the GnomAD database, including 10,787 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 0.30 (10787 hom., cov: 32)
• Consequence: BRAF NM_001374258.1 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.51
• Publications: 6 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=-0.95).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.658 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001374258.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	BRAF	NM_001374258.1	MANE Plus Clinical	c.1815-940C>A		intron	N/A	NP_001361187.1
	BRAF	NM_004333.6	MANE Select	c.1695-940C>A		intron	N/A	NP_004324.2
	BRAF	NM_001374244.1		c.1815-940C>A		intron	N/A	NP_001361173.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	BRAF	ENST00000644969.2	MANE Plus Clinical	c.1815-940C>A		intron	N/A	ENSP00000496776.1
	BRAF	ENST00000646891.2	MANE Select	c.1695-940C>A		intron	N/A	ENSP00000493543.1
	BRAF	ENST00000288602.11	TSL:1	c.1815-940C>A		intron	N/A	ENSP00000288602.7

Frequencies

GnomAD3 genomes AF: 0.298 AC: 45243 AN: 151912 Hom.: 10738 Cov.: 32

Gnomad AFR AF: 0.664

Gnomad AMI AF: 0.104

Gnomad AMR AF: 0.181

Gnomad ASJ AF: 0.199

Gnomad EAS AF: 0.174

Gnomad SAS AF: 0.309

Gnomad FIN AF: 0.152

Gnomad MID AF: 0.307

Gnomad NFE AF: 0.142

Gnomad OTH AF: 0.267

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

GnomAD4 genome AF: 0.298 AC: 45341 AN: 152030 Hom.: 10787 Cov.: 32 AF XY: 0.296 AC XY: 21992 AN XY: 74326

African (AFR) AF: 0.664 AC: 27514 AN: 41424

American (AMR) AF: 0.180 AC: 2758 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.199 AC: 687 AN: 3460

East Asian (EAS) AF: 0.174 AC: 901 AN: 5174

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

European-Finnish (FIN) AF: 0.152 AC: 1610 AN: 10558

Middle Eastern (MID) AF: 0.310 AC: 91 AN: 294

European-Non Finnish (NFE) AF: 0.142 AC: 9636 AN: 67996

Other (OTH) AF: 0.268 AC: 565 AN: 2108

Alfa AF: 0.162 Hom.: 1252

Bravo AF: 0.312

Asia WGS AF: 0.279 AC: 973 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.95
CADD	Benign	0.14
DANN	Benign	0.43
PhyloP100		-1.5
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: rs7801086; hg19: chr7-140454973;