rs371877084

Variant names:

• chr7-140924626-C-A
• rs371877084
• NM_001374258.1:c.78G>T

Your query was ambiguous. Multiple possible variants found:

• chr7-140924626-C-A
• chr7-140924626-C-T

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 1P and 20B. PP2 BP4_Strong BP6_Very_Strong BS1 BS2

The NM_004333.6(BRAF):​c.78G>T​(p.Glu26Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00188 in 1,519,096 control chromosomes in the GnomAD database, including 50 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E26K) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.010 (30 hom., cov: 31)
  • Exomes 𝑓: 0.00098 (20 hom.)
• Consequence: BRAF NM_004333.6 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:19 O:1
• Conservation: PhyloP100: 0.916
• Publications: 14 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 -19 ACMG points.

• PP2: Missense variant in the BRAF gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 139 curated pathogenic missense variants (we use a threshold of 10). The gene has 21 curated benign missense variants. Gene score misZ: 3.7208 (above the threshold of 3.09). Trascript score misZ: 4.9447 (above the threshold of 3.09). GenCC associations: The gene is linked to cardiofaciocutaneous syndrome, Noonan syndrome with multiple lentigines, Noonan syndrome, cardiofaciocutaneous syndrome 1, Noonan syndrome 7, LEOPARD syndrome 3, anaplastic astrocytoma, Costello syndrome.
• BP4: Computational evidence support a benign effect (MetaRNN=0.00439623).
• BP6: Variant 7-140924626-C-A is Benign according to our data. Variant chr7-140924626-C-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 40337.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.01 (1516/150966) while in subpopulation AFR AF = 0.0351 (1445/41202). AF 95% confidence interval is 0.0336. There are 30 homozygotes in GnomAd4. There are 711 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.
• BS2: High AC in GnomAd4 at 1516 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.78G>T	p.Glu26Asp	missense	Exon 1 of 20	NP_001361187.1	A0A2R8Y8E0
	BRAF	NM_004333.6	MANE Select	c.78G>T	p.Glu26Asp	missense	Exon 1 of 18	NP_004324.2
	BRAF	NM_001374244.1		c.78G>T	p.Glu26Asp	missense	Exon 1 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.78G>T	p.Glu26Asp	missense	Exon 1 of 20	ENSP00000496776.1	A0A2R8Y8E0
	BRAF	ENST00000646891.2	MANE Select	c.78G>T	p.Glu26Asp	missense	Exon 1 of 18	ENSP00000493543.1	P15056
	BRAF	ENST00000288602.11	TSL:1	c.78G>T	p.Glu26Asp	missense	Exon 1 of 19	ENSP00000288602.7	A0A2U3TZI2

Frequencies

GnomAD3 genomes AF: 0.0100 AC: 1515 AN: 150862 Hom.: 30 Cov.: 31

Gnomad AFR AF: 0.0351

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00289

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00980

Gnomad NFE AF: 0.000163

Gnomad OTH AF: 0.00624

GnomAD2 exomes AF: 0.00235 AC: 296 AN: 125944 AF XY: 0.00168

Gnomad AFR exome AF: 0.0409

Gnomad AMR exome AF: 0.00204

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000107

Gnomad OTH exome AF: 0.00102

GnomAD4 exome AF: 0.000985 AC: 1347 AN: 1368130 Hom.: 20 Cov.: 30 AF XY: 0.000820 AC XY: 554 AN XY: 675502

African (AFR) AF: 0.0343 AC: 1059 AN: 30898

American (AMR) AF: 0.00244 AC: 86 AN: 35250

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24964

East Asian (EAS) AF: 0.00 AC: 0 AN: 35442

South Asian (SAS) AF: 0.0000381 AC: 3 AN: 78792

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 33388

Middle Eastern (MID) AF: 0.00122 AC: 5 AN: 4092

European-Non Finnish (NFE) AF: 0.0000796 AC: 85 AN: 1068176

Other (OTH) AF: 0.00191 AC: 109 AN: 57128

GnomAD4 genome AF: 0.0100 AC: 1516 AN: 150966 Hom.: 30 Cov.: 31 AF XY: 0.00964 AC XY: 711 AN XY: 73790

African (AFR) AF: 0.0351 AC: 1445 AN: 41202

American (AMR) AF: 0.00289 AC: 44 AN: 15228

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3462

East Asian (EAS) AF: 0.00 AC: 0 AN: 4976

South Asian (SAS) AF: 0.00 AC: 0 AN: 4790

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10462

Middle Eastern (MID) AF: 0.0106 AC: 3 AN: 284

European-Non Finnish (NFE) AF: 0.000163 AC: 11 AN: 67554

Other (OTH) AF: 0.00618 AC: 13 AN: 2104

Alfa AF: 0.00522 Hom.: 1

Bravo AF: 0.0113

ESP6500AA AF: 0.0174 AC: 26

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000634 AC: 22

Asia WGS AF: 0.00173 AC: 6 AN: 3472

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	6	not specified (7)
-	-	5	not provided (5)
-	-	2	RASopathy (2)
-	-	1	Cardiofaciocutaneous syndrome 1 (1)
-	-	1	Cardiovascular phenotype (1)
-	-	1	LEOPARD syndrome 3 (1)
-	-	1	Noonan syndrome (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
AlphaMissense	Benign	0.092
BayesDel_addAF	Benign	-0.33	T
BayesDel_noAF	Benign	-0.22
CADD	Benign	20
DANN	Uncertain	0.98
DEOGEN2	Benign	0.29	T
Eigen	Benign	-0.40
Eigen_PC	Benign	-0.28
FATHMM_MKL	Benign	0.39	N
LIST_S2	Benign	0.80	T
MetaRNN	Benign	0.0044	T
MetaSVM	Benign	-0.88	T
MutationAssessor	Benign	0.0	N
PhyloP100		0.92
PrimateAI	Pathogenic	0.92	D
PROVEAN	Benign	-0.18	N
REVEL	Benign	0.17
Sift	Benign	0.17	T
Sift4G	Benign	0.27	T
Polyphen		0.37	B
Vest4		0.32
MutPred		0.16		Loss of helix (P = 0.0093)
MVP		0.58
MPC		0.86
ClinPred		0.040	T
GERP RS		2.3
PromoterAI		-0.11	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.077
gMVP		0.17
Mutation Taster		=99/1	polymorphism

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: rs371877084; hg19: chr7-140624426; COSMIC: COSV56062586;