7-140781618-C-G

Variant names:

• chr7-140781618-C-G
• rs121913349
• NM_001374258.1:c.1510G>C

Variant summary

Our verdict is Pathogenic. Variant got 21 ACMG points: 21P and 0B. PS1_Very_Strong PM1 PM2 PM5 PP2 PP3_Strong PP5_Moderate

The NM_004333.6(BRAF):​c.1390G>C​(p.Gly464Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 12/19 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Pathogenic in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G464E) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: BRAF NM_004333.6 missense
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 7.89

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]

ENSG00000289788 (HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 21 ACMG points.

• PS1: Transcript NM_004333.6 (BRAF) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in ClinVar as 372572
• PM1: In a hotspot region, there are 8 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 12 uncertain in NM_004333.6
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr7-140781617-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 13964.Status of the report is reviewed_by_expert_panel, 3 stars.
• 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 LEOPARD syndrome 3, anaplastic astrocytoma, Noonan syndrome with multiple lentigines, cardiofaciocutaneous syndrome 1, Noonan syndrome, cardiofaciocutaneous syndrome, Costello syndrome, Noonan syndrome 7.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.988
• PP5: Variant 7-140781618-C-G is Pathogenic according to our data. Variant chr7-140781618-C-G is described in ClinVar as [Pathogenic]. Clinvar id is 279992.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
BRAF	NM_001374258.1	c.1510G>C	p.Gly504Arg	missense_variant	Exon 12 of 20	ENST00000644969.2	NP_001361187.1
BRAF	NM_004333.6	c.1390G>C	p.Gly464Arg	missense_variant	Exon 11 of 18	ENST00000646891.2	NP_004324.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
BRAF	ENST00000644969.2	c.1510G>C	p.Gly504Arg	missense_variant	Exon 12 of 20		NM_001374258.1	ENSP00000496776.1
BRAF	ENST00000646891.2	c.1390G>C	p.Gly464Arg	missense_variant	Exon 11 of 18		NM_004333.6	ENSP00000493543.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Pathogenic:1

Apr 18, 2017

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The G464R pathogenic variant has been reported previously in association with a BRAF-related disorder (Nava et al., 2007). The G464R variant was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The G464R variant is a non-conservative amino acid substitution that occurs at a position that is conserved across species. In silico analysis predicts this variant is probably damaging to the protein structure/function. Missense variants in nearby residues (F468S, G469R, G469E) have been reported in the Human Gene Mutation Database in association with cardio-facio-cutaneous syndrome (Stenson et al., 2014), supporting the functional importance of this region of the protein. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.49	D
BayesDel_noAF	Pathogenic	0.46
CADD	Pathogenic	32
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.95	.;.;D;.
Eigen	Pathogenic	0.74
Eigen_PC	Pathogenic	0.74
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.99	D;D;D;D
M_CAP	Pathogenic	0.45	D
MetaRNN	Pathogenic	0.99	D;D;D;D
MetaSVM	Uncertain	0.59	D
MutationAssessor	Pathogenic	3.3	.;.;M;.
PrimateAI	Pathogenic	0.89	D
REVEL	Pathogenic	0.94
Polyphen		1.0	.;.;D;.
MutPred		0.98		Gain of MoRF binding (P = 0.0264);.;Gain of MoRF binding (P = 0.0264);.;
MVP		0.99
MPC		2.3
ClinPred		1.0	D
GERP RS		5.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.98
gMVP		0.89

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

Publications

LitVar

Other links and lift over

dbSNP: rs121913349; hg19: chr7-140481418; COSMIC: COSV56361117;