rs71645981

Variant names:

• chr7-140777956-C-G
• rs71645981
• NM_001374258.1:c.1637+35G>C

Your query was ambiguous. Multiple possible variants found:

• chr7-140777956-C-G
• chr7-140777956-C-T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001374258.1(BRAF):​c.1637+35G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0185 in 1,598,902 control chromosomes in the GnomAD database, including 385 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.015 (26 hom., cov: 32)
  • Exomes 𝑓: 0.019 (359 hom.)
• Consequence: BRAF NM_001374258.1 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.201
• 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

ENSG00000289788 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.78).
• BP6: Variant 7-140777956-C-G is Benign according to our data. Variant chr7-140777956-C-G is described in ClinVar as Benign. ClinVar VariationId is 40376.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.0147 (2241/152270) while in subpopulation AMR AF = 0.0247 (377/15290). AF 95% confidence interval is 0.0226. There are 26 homozygotes in GnomAd4. There are 1064 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 2241 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
BRAF	NM_001374258.1	c.1637+35G>C		intron_variant	Intron 13 of 19	ENST00000644969.2	NP_001361187.1
BRAF	NM_004333.6	c.1517+35G>C		intron_variant	Intron 12 of 17	ENST00000646891.2	NP_004324.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
BRAF	ENST00000644969.2	c.1637+35G>C		intron_variant	Intron 13 of 19		NM_001374258.1	ENSP00000496776.1
BRAF	ENST00000646891.2	c.1517+35G>C		intron_variant	Intron 12 of 17		NM_004333.6	ENSP00000493543.1

Frequencies

GnomAD3 genomes AF: 0.0147 AC: 2242 AN: 152152 Hom.: 25 Cov.: 32

Gnomad AFR AF: 0.00432

Gnomad AMI AF: 0.00658

Gnomad AMR AF: 0.0247

Gnomad ASJ AF: 0.0363

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00207

Gnomad FIN AF: 0.00386

Gnomad MID AF: 0.0253

Gnomad NFE AF: 0.0213

Gnomad OTH AF: 0.0220

GnomAD2 exomes AF: 0.0138 AC: 3458 AN: 249992 AF XY: 0.0143

Gnomad AFR exome AF: 0.00322

Gnomad AMR exome AF: 0.0118

Gnomad ASJ exome AF: 0.0375

Gnomad EAS exome AF: 0.0000545

Gnomad FIN exome AF: 0.00363

Gnomad NFE exome AF: 0.0207

Gnomad OTH exome AF: 0.0178

GnomAD4 exome AF: 0.0189 AC: 27379 AN: 1446632 Hom.: 359 Cov.: 28 AF XY: 0.0186 AC XY: 13372 AN XY: 720664

African (AFR) AF: 0.00281 AC: 93 AN: 33108

American (AMR) AF: 0.0124 AC: 553 AN: 44592

Ashkenazi Jewish (ASJ) AF: 0.0372 AC: 968 AN: 26012

East Asian (EAS) AF: 0.00 AC: 0 AN: 39514

South Asian (SAS) AF: 0.00309 AC: 265 AN: 85874

European-Finnish (FIN) AF: 0.00374 AC: 199 AN: 53176

Middle Eastern (MID) AF: 0.0198 AC: 108 AN: 5446

European-Non Finnish (NFE) AF: 0.0218 AC: 23955 AN: 1099062

Other (OTH) AF: 0.0207 AC: 1238 AN: 59848

GnomAD4 genome AF: 0.0147 AC: 2241 AN: 152270 Hom.: 26 Cov.: 32 AF XY: 0.0143 AC XY: 1064 AN XY: 74444

African (AFR) AF: 0.00431 AC: 179 AN: 41566

American (AMR) AF: 0.0247 AC: 377 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.0363 AC: 126 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.00166 AC: 8 AN: 4820

European-Finnish (FIN) AF: 0.00386 AC: 41 AN: 10612

Middle Eastern (MID) AF: 0.0272 AC: 8 AN: 294

European-Non Finnish (NFE) AF: 0.0213 AC: 1448 AN: 68004

Other (OTH) AF: 0.0227 AC: 48 AN: 2116

Alfa AF: 0.0201 Hom.: 8

Bravo AF: 0.0155

Asia WGS AF: 0.00231 AC: 8 AN: 3476

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Mar 03, 2015

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

not specified Benign:1

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.78
CADD	Benign	2.6
DANN	Benign	0.78
PhyloP100		0.20
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: rs71645981; hg19: chr7-140477756; COSMIC: COSV56338562;