NM_001374258.1:c.2256C>T

Variant names:

• chr7-140734762-G-A
• rs377165711
• NM_001374258.1:c.2256C>T

Variant summary

Our verdict is Benign. The variant received -15 ACMG points: 0P and 15B. BP4_Moderate BP6_Very_Strong BP7 BS2

The NM_001374258.1(BRAF):​c.2256C>T​(p.Ala752Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000777 in 1,429,086 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 Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.000024 (0 hom., cov: 24)
  • Exomes 𝑓: 0.000083 (0 hom.)
• Consequence: BRAF NM_001374258.1 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 2.67
• 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

Our verdict: Benign. The variant received -15 ACMG points.

• BP4: Computational evidence support a benign effect (REVEL=0.049).
• BP6: Variant 7-140734762-G-A is Benign according to our data. Variant chr7-140734762-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 44823.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=2.67 with no splicing effect.
• BS2: High AC in GnomAdExome4 at 108 AD gene.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	BRAF	NM_001374258.1	MANE Plus Clinical	c.2256C>T	p.Ala752Ala	synonymous	Exon 19 of 20	NP_001361187.1	A0A2R8Y8E0
	BRAF	NM_004333.6	MANE Select	c.2136C>T	p.Ala712Ala	synonymous	Exon 18 of 18	NP_004324.2
	BRAF	NM_001374244.1		c.2256C>T	p.Ala752Ala	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.2256C>T	p.Ala752Ala	synonymous	Exon 19 of 20	ENSP00000496776.1	A0A2R8Y8E0
	BRAF	ENST00000646891.2	MANE Select	c.2136C>T	p.Ala712Ala	synonymous	Exon 18 of 18	ENSP00000493543.1	P15056
	BRAF	ENST00000288602.11	TSL:1	c.2256C>T	p.Ala752Ala	synonymous	Exon 19 of 19	ENSP00000288602.7	A0A2U3TZI2

Frequencies

GnomAD3 genomes AF: 0.0000243 AC: 3 AN: 123250 Hom.: 0 Cov.: 24

Gnomad AFR AF: 0.00

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: 0.0000499

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000624 AC: 11 AN: 176228 AF XY: 0.0000308

Gnomad AFR exome AF: 0.00

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: 0.000126

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000827 AC: 108 AN: 1305836 Hom.: 0 Cov.: 35 AF XY: 0.0000714 AC XY: 46 AN XY: 644240

African (AFR) AF: 0.00 AC: 0 AN: 28384

American (AMR) AF: 0.00 AC: 0 AN: 28194

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 21520

East Asian (EAS) AF: 0.00 AC: 0 AN: 33340

South Asian (SAS) AF: 0.00 AC: 0 AN: 54570

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 47180

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5216

European-Non Finnish (NFE) AF: 0.000103 AC: 107 AN: 1034524

Other (OTH) AF: 0.0000189 AC: 1 AN: 52908

GnomAD4 genome AF: 0.0000243 AC: 3 AN: 123250 Hom.: 0 Cov.: 24 AF XY: 0.0000172 AC XY: 1 AN XY: 58198

African (AFR) AF: 0.00 AC: 0 AN: 32014

American (AMR) AF: 0.00 AC: 0 AN: 10770

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3204

East Asian (EAS) AF: 0.00 AC: 0 AN: 4452

South Asian (SAS) AF: 0.00 AC: 0 AN: 3988

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6114

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 204

European-Non Finnish (NFE) AF: 0.0000499 AC: 3 AN: 60148

Other (OTH) AF: 0.00 AC: 0 AN: 1568

Alfa AF: 0.0000301 Hom.: 0

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	Cardiovascular phenotype (1)
-	-	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 (1)
-	-	1	not specified (1)
-	-	1	RASopathy (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.47
CADD	Benign	13
DANN	Benign	0.49
PhyloP100		2.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=99/1	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs377165711; hg19: chr7-140434562;