rs1554399258

Variant names:

• chr7-140778020-T-G
• rs1554399258
• NM_001374258.1:c.1608A>C

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM1 PM2 PP2

The NM_004333.6(BRAF):​c.1488A>C​(p.Gln496His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: BRAF NM_004333.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.30

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 Uncertain_significance. Variant got 5 ACMG points.

• PM1: In a domain Protein kinase (size 260) in uniprot entity BRAF_HUMAN there are 21 pathogenic changes around while only 1 benign (95%) in NM_004333.6
• PM2: Very rare variant in population databases, with high coverage
• 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
BRAF	NM_001374258.1	c.1608A>C	p.Gln536His	missense_variant	Exon 13 of 20	ENST00000644969.2	NP_001361187.1
BRAF	NM_004333.6	c.1488A>C	p.Gln496His	missense_variant	Exon 12 of 18	ENST00000646891.2	NP_004324.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
BRAF	ENST00000644969.2	c.1608A>C	p.Gln536His	missense_variant	Exon 13 of 20		NM_001374258.1	ENSP00000496776.1
BRAF	ENST00000646891.2	c.1488A>C	p.Gln496His	missense_variant	Exon 12 of 18		NM_004333.6	ENSP00000493543.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Mar 06, 2018

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: not in Gnomad with coverage; not in ClinVar or HGMD or google search, conflicting in silico predictions, conserved. Identified in 1 individual with HCM. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.93
BayesDel_addAF	Uncertain	0.12	D
BayesDel_noAF	Uncertain	-0.070
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.85	.;.;D;.
Eigen	Benign	0.038
Eigen_PC	Benign	0.088
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Uncertain	0.97	D;D;D;D
M_CAP	Uncertain	0.11	D
MetaRNN	Uncertain	0.56	D;D;D;D
MetaSVM	Uncertain	-0.26	T
MutationAssessor	Benign	1.4	.;.;L;.
PrimateAI	Pathogenic	0.90	D
REVEL	Uncertain	0.55
Polyphen		0.42	.;.;B;.
MutPred		0.43		Loss of methylation at K499 (P = 0.1401);.;Loss of methylation at K499 (P = 0.1401);.;
MVP		0.72
MPC		1.8
ClinPred		1.0	D
GERP RS		3.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.95
gMVP		0.63

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: rs1554399258; hg19: chr7-140477820;