rs3789806

Variant names:

• chr7-140749271-C-G
• rs3789806
• NM_001374258.1:c.2112+16G>C

Your query was ambiguous. Multiple possible variants found:

• chr7-140749271-C-G
• chr7-140749271-C-T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_004333.6(BRAF):​c.1992+16G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.176 in 1,609,598 control chromosomes in the GnomAD database, including 37,044 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.30 (10808 hom., cov: 32)
  • Exomes 𝑓: 0.16 (26236 hom.)
• Consequence: BRAF NM_004333.6 intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9 O:1
• Conservation: PhyloP100: 0.313
• Publications: 17 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: G2P, Ambry Genetics, Labcorp Genetics (formerly Invitae), Genomics England PanelApp
• LEOPARD syndrome 3

  Inheritance: AD Classification: DEFINITIVE, STRONG, LIMITED Submitted by: Genomics England PanelApp, Labcorp Genetics (formerly Invitae), G2P, Ambry Genetics
• Noonan syndrome 7

  Inheritance: AD Classification: DEFINITIVE, STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), G2P, Genomics England PanelApp, Ambry Genetics
• 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
• Noonan syndrome-like disorder with loose anagen hair

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.89).
• BP6: Variant 7-140749271-C-G is Benign according to our data. Variant chr7-140749271-C-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 40393.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• 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_004333.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	BRAF	NM_001374258.1	MANE Plus Clinical	c.2112+16G>C		intron	N/A	NP_001361187.1	A0A2R8Y8E0
	BRAF	NM_004333.6	MANE Select	c.1992+16G>C		intron	N/A	NP_004324.2
	BRAF	NM_001374244.1		c.2112+16G>C		intron	N/A	NP_001361173.1	A0A2U3TZI2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	BRAF	ENST00000644969.2	MANE Plus Clinical	c.2112+16G>C		intron	N/A	ENSP00000496776.1	A0A2R8Y8E0
	BRAF	ENST00000646891.2	MANE Select	c.1992+16G>C		intron	N/A	ENSP00000493543.1	P15056
	BRAF	ENST00000288602.11	TSL:1	c.2112+16G>C		intron	N/A	ENSP00000288602.7	A0A2U3TZI2

Frequencies

GnomAD3 genomes AF: 0.298 AC: 45280 AN: 151876 Hom.: 10759 Cov.: 32

Gnomad AFR AF: 0.664

Gnomad AMI AF: 0.104

Gnomad AMR AF: 0.181

Gnomad ASJ AF: 0.198

Gnomad EAS AF: 0.174

Gnomad SAS AF: 0.310

Gnomad FIN AF: 0.153

Gnomad MID AF: 0.304

Gnomad NFE AF: 0.142

Gnomad OTH AF: 0.267

GnomAD2 exomes AF: 0.199 AC: 49747 AN: 250290 AF XY: 0.199

Gnomad AFR exome AF: 0.674

Gnomad AMR exome AF: 0.0994

Gnomad ASJ exome AF: 0.205

Gnomad EAS exome AF: 0.186

Gnomad FIN exome AF: 0.149

Gnomad NFE exome AF: 0.142

Gnomad OTH exome AF: 0.179

GnomAD4 exome AF: 0.163 AC: 237989 AN: 1457604 Hom.: 26236 Cov.: 32 AF XY: 0.167 AC XY: 121127 AN XY: 725174

African (AFR) AF: 0.680 AC: 22655 AN: 33324

American (AMR) AF: 0.109 AC: 4878 AN: 44640

Ashkenazi Jewish (ASJ) AF: 0.206 AC: 5361 AN: 26064

East Asian (EAS) AF: 0.156 AC: 6159 AN: 39540

South Asian (SAS) AF: 0.313 AC: 26966 AN: 86054

European-Finnish (FIN) AF: 0.142 AC: 7570 AN: 53248

Middle Eastern (MID) AF: 0.283 AC: 1175 AN: 4146

European-Non Finnish (NFE) AF: 0.136 AC: 151504 AN: 1110504

Other (OTH) AF: 0.195 AC: 11721 AN: 60084

GnomAD4 genome AF: 0.299 AC: 45378 AN: 151994 Hom.: 10808 Cov.: 32 AF XY: 0.296 AC XY: 21990 AN XY: 74278

African (AFR) AF: 0.665 AC: 27556 AN: 41456

American (AMR) AF: 0.180 AC: 2753 AN: 15266

Ashkenazi Jewish (ASJ) AF: 0.198 AC: 687 AN: 3468

East Asian (EAS) AF: 0.174 AC: 900 AN: 5168

South Asian (SAS) AF: 0.309 AC: 1488 AN: 4818

European-Finnish (FIN) AF: 0.153 AC: 1612 AN: 10568

Middle Eastern (MID) AF: 0.306 AC: 90 AN: 294

European-Non Finnish (NFE) AF: 0.142 AC: 9632 AN: 67936

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

Alfa AF: 0.125 Hom.: 340

Bravo AF: 0.312

Asia WGS AF: 0.280 AC: 974 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	not specified (5)
-	-	2	RASopathy (2)
-	-	1	Lung cancer;C0346629:Colorectal cancer;C1835047:Melanoma, cutaneous malignant, susceptibility to, 1;C3150970:Noonan syndrome 7;C3150971:LEOPARD syndrome 3;C4551602:Noonan syndrome 1;CN029449:Cardiofaciocutaneous syndrome 1 (1)
-	-	1	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	12
DANN	Benign	0.50
PhyloP100		0.31
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: rs3789806; hg19: chr7-140449071; COSMIC: COSV56062530;