NM_001374258.1:c.1347A>G

Variant names:

• chr7-140783108-T-C
• rs145035762
• NM_001374258.1:c.1347A>G

Variant summary

Our verdict is Benign. The variant received -11 ACMG points: 0P and 11B. BA1 BP4 BP7 BP5

This summary comes from the ClinGen Evidence Repository: The filtering allele frequency of the c.1227A>G (p.Ser409=) variant in the BRAF gene is 0.313% for European (Non-Finnish) chromosomes by the Exome Aggregation Consortium (233/66620 with 95% CI), which is a high enough frequency to be classified as benign based on thresholds defined by the ClinGen RASopathy Expert panel for autosomal dominant RASopathy variants (BA1). Additionally, this variant is a synonymous (silent) variant at a nucleotide that is not highly conserved and is not predicted to impact splicing (BP7). The p.Ser409= variant has been identified in a patient with an alternate molecular basis for disease (BP5; GeneDx, Partners LMM, EGL Genetics internal data; GTR ID's: 21766, 26957, 500060; SCV000057203.8; SCV000061570.5; SCV000112807.7). Computational prediction tools and conservation analysis suggest that the p.Ser409= variant does not impact the protein (BP4). In summary, this variant meets criteria to be classified as benign. ACMG/AMP criteria applied: BA1, BP7, BP5, BP4. LINK:https://erepo.genome.network/evrepo/ui/classification/CA135058/MONDO:0021060/004

• Frequency:
  • Genomes: 𝑓 0.0027 (2 hom., cov: 32)
  • Exomes 𝑓: 0.0034 (17 hom.)
• Consequence: BRAF NM_001374258.1 synonymous
• Clinical Significance: Benign reviewed by expert panel B:14
• Conservation: PhyloP100: -0.0270
• Publications: 3 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 -11 ACMG points.

• BP4: For more information check the summary or visit ClinGen Evidence Repository.
• BP5: For more information check the summary or visit ClinGen Evidence Repository.
• BP7: For more information check the summary or visit ClinGen Evidence Repository.
• BA1: For more information check the summary or visit ClinGen Evidence Repository.

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.1347A>G	p.Ser449Ser	synonymous	Exon 11 of 20	NP_001361187.1
	BRAF	NM_004333.6	MANE Select	c.1227A>G	p.Ser409Ser	synonymous	Exon 10 of 18	NP_004324.2
	BRAF	NM_001374244.1		c.1347A>G	p.Ser449Ser	synonymous	Exon 11 of 19	NP_001361173.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	BRAF	ENST00000644969.2	MANE Plus Clinical	c.1347A>G	p.Ser449Ser	synonymous	Exon 11 of 20	ENSP00000496776.1
	BRAF	ENST00000646891.2	MANE Select	c.1227A>G	p.Ser409Ser	synonymous	Exon 10 of 18	ENSP00000493543.1
	BRAF	ENST00000288602.11	TSL:1	c.1347A>G	p.Ser449Ser	synonymous	Exon 11 of 19	ENSP00000288602.7

Frequencies

GnomAD3 genomes AF: 0.00269 AC: 410 AN: 152174 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.000676

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000196

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0140

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00338

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00318 AC: 799 AN: 251410 AF XY: 0.00308

Gnomad AFR exome AF: 0.000923

Gnomad AMR exome AF: 0.000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0165

Gnomad NFE exome AF: 0.00341

Gnomad OTH exome AF: 0.00456

GnomAD4 exome AF: 0.00342 AC: 5004 AN: 1461794 Hom.: 17 Cov.: 30 AF XY: 0.00342 AC XY: 2485 AN XY: 727192

African (AFR) AF: 0.000627 AC: 21 AN: 33478

American (AMR) AF: 0.000246 AC: 11 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.0000383 AC: 1 AN: 26132

East Asian (EAS) AF: 0.00 AC: 0 AN: 39674

South Asian (SAS) AF: 0.0000232 AC: 2 AN: 86254

European-Finnish (FIN) AF: 0.0166 AC: 886 AN: 53412

Middle Eastern (MID) AF: 0.000173 AC: 1 AN: 5764

European-Non Finnish (NFE) AF: 0.00353 AC: 3927 AN: 1111970

Other (OTH) AF: 0.00257 AC: 155 AN: 60392

GnomAD4 genome AF: 0.00269 AC: 410 AN: 152292 Hom.: 2 Cov.: 32 AF XY: 0.00318 AC XY: 237 AN XY: 74454

African (AFR) AF: 0.000674 AC: 28 AN: 41548

American (AMR) AF: 0.000196 AC: 3 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

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

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.0140 AC: 149 AN: 10612

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00338 AC: 230 AN: 68030

Other (OTH) AF: 0.00 AC: 0 AN: 2114

Alfa AF: 0.00257 Hom.: 0

Bravo AF: 0.00172

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00333

EpiControl AF: 0.00279

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
-	-	4	not provided (4)
-	-	4	not specified (4)
-	-	2	RASopathy (2)
-	-	1	Cardiovascular phenotype (1)
-	-	1	LEOPARD syndrome 3 (1)
-	-	1	Noonan syndrome 7 (1)
-	-	1	Noonan syndrome and Noonan-related syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.48
CADD	Benign	7.6
DANN	Benign	0.72
PhyloP100		-0.027
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=100/0	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: rs145035762; hg19: chr7-140482908; COSMIC: COSV104608176;