7-140734702-G-C

Variant names:

• chr7-140734702-G-C
• rs142592480
• NM_001374258.1:c.2316C>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Moderate BP6 BP7 BS1 BS2

The NM_004333.6(BRAF):​c.2196C>G​(p.Ser732Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000124 in 1,612,072 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). The gene BRAF is included in the ClinGen Criteria Specification Registry.

• Frequency:
  • Genomes: 𝑓 0.000040 (0 hom., cov: 31)
  • Exomes 𝑓: 0.00013 (0 hom.)
• Consequence: BRAF NM_004333.6 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:6
• Conservation: PhyloP100: -0.184
• Publications: 0 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

Specifications for BRAF are available in the ClinGen Criteria Specification Registry and recommended for reference when assigning criteria.

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (REVEL=0.06).
• BP6: Variant 7-140734702-G-C is Benign according to our data. Variant chr7-140734702-G-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 417227.
• BP7: Synonymous conserved (PhyloP=-0.184 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. GnomAdExome4 allele frequency = 0.000133 (194/1461864) while in subpopulation NFE AF = 0.000168 (187/1112000). AF 95% confidence interval is 0.000148. There are 0 homozygotes in GnomAdExome4. There are 88 alleles in the male GnomAdExome4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High AC in GnomAd4 at 6 AD gene.

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.2316C>G	p.Ser772Ser	synonymous	Exon 19 of 20	NP_001361187.1	A0A2R8Y8E0
	BRAF	NM_004333.6	MANE Select	c.2196C>G	p.Ser732Ser	synonymous	Exon 18 of 18	NP_004324.2
	BRAF	NM_001374244.1		c.2316C>G	p.Ser772Ser	synonymous	Exon 19 of 19	NP_001361173.1	A0A2U3TZI2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	BRAF	ENST00000644969.2	MANE Plus Clinical	c.2316C>G	p.Ser772Ser	synonymous	Exon 19 of 20	ENSP00000496776.1	A0A2R8Y8E0
	BRAF	ENST00000646891.2	MANE Select	c.2196C>G	p.Ser732Ser	synonymous	Exon 18 of 18	ENSP00000493543.1	P15056
	BRAF	ENST00000288602.11	TSL:1	c.2316C>G	p.Ser772Ser	synonymous	Exon 19 of 19	ENSP00000288602.7	A0A2U3TZI2

Frequencies

GnomAD3 genomes AF: 0.0000399 AC: 6 AN: 150208 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.0000246

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000738

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000596 AC: 15 AN: 251484 AF XY: 0.0000589

Gnomad AFR exome AF: 0.000123

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000105

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.000133 AC: 194 AN: 1461864 Hom.: 0 Cov.: 33 AF XY: 0.000121 AC XY: 88 AN XY: 727234

African (AFR) AF: 0.0000597 AC: 2 AN: 33478

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53410

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.000168 AC: 187 AN: 1112000

Other (OTH) AF: 0.0000828 AC: 5 AN: 60392

GnomAD4 genome AF: 0.0000399 AC: 6 AN: 150208 Hom.: 0 Cov.: 31 AF XY: 0.0000410 AC XY: 3 AN XY: 73136

African (AFR) AF: 0.0000246 AC: 1 AN: 40702

American (AMR) AF: 0.00 AC: 0 AN: 15026

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5142

South Asian (SAS) AF: 0.00 AC: 0 AN: 4780

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10050

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 314

European-Non Finnish (NFE) AF: 0.0000738 AC: 5 AN: 67784

Other (OTH) AF: 0.00 AC: 0 AN: 2034

Alfa AF: 0.0000947 Hom.: 0

EpiCase AF: 0.000164

EpiControl AF: 0.0000593

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	BRAF-related disorder (1)
-	-	1	Cardiovascular phenotype (1)
-	1	-	LEOPARD syndrome 3 (1)
-	1	-	Noonan syndrome 7 (1)
-	-	1	not specified (1)
-	-	1	RASopathy (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.49
CADD	Benign	11
DANN	Benign	0.69
PhyloP100		-0.18

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: rs142592480; hg19: chr7-140434502; COSMIC: COSV56253634;