rs1554404461

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 3P and 1B. PM2PP2BP4

The NM_004333.6(BRAF):​c.653C>G​(p.Thr218Ser) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Consequence

BRAF
NM_004333.6 missense

Scores

2
5
12

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 5.89
Variant links:
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP2
Missense variant in gene, where missense usually causes diseases (based on misZ statistic), BRAF. . Gene score misZ 3.7208 (greater than the threshold 3.09). Trascript score misZ 4.9447 (greater than threshold 3.09). GenCC has associacion of gene with LEOPARD syndrome 3, anaplastic astrocytoma, Noonan syndrome with multiple lentigines, cardiofaciocutaneous syndrome 1, Noonan syndrome, cardiofaciocutaneous syndrome, Costello syndrome, Noonan syndrome 7.
BP4
Computational evidence support a benign effect (MetaRNN=0.3463982).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
BRAFNM_001374258.1 linkuse as main transcriptc.653C>G p.Thr218Ser missense_variant 5/20 ENST00000644969.2 NP_001361187.1
BRAFNM_004333.6 linkuse as main transcriptc.653C>G p.Thr218Ser missense_variant 5/18 ENST00000646891.2 NP_004324.2

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
BRAFENST00000644969.2 linkuse as main transcriptc.653C>G p.Thr218Ser missense_variant 5/20 NM_001374258.1 ENSP00000496776
BRAFENST00000646891.2 linkuse as main transcriptc.653C>G p.Thr218Ser missense_variant 5/18 NM_004333.6 ENSP00000493543 P4

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
Cov.:
30
GnomAD4 genome
Cov.:
32

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not specified Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingLaboratory for Molecular Medicine, Mass General Brigham Personalized MedicineDec 23, 2016The p.Thr218Ser variant in BRAF has not been previously reported in individuals with clinical features of a RASopathy and was absent from large population studi es. Computational prediction tools and conservation analysis do not provide stro ng support for or against an impact to the protein. In summary, the clinical sig nificance of the p.Thr218Ser variant is uncertain. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Uncertain
0.43
BayesDel_addAF
Uncertain
0.027
T
BayesDel_noAF
Benign
-0.20
CADD
Uncertain
25
DANN
Uncertain
0.98
DEOGEN2
Benign
0.31
.;.;T;.
Eigen
Benign
0.071
Eigen_PC
Benign
0.21
FATHMM_MKL
Pathogenic
0.98
D
LIST_S2
Uncertain
0.93
D;D;D;D
M_CAP
Benign
0.012
T
MetaRNN
Benign
0.35
T;T;T;T
MetaSVM
Benign
-0.82
T
MutationAssessor
Benign
0.69
.;.;N;.
MutationTaster
Benign
1.0
D
PrimateAI
Pathogenic
0.82
D
PROVEAN
Benign
-0.34
.;.;.;N
REVEL
Uncertain
0.34
Sift
Benign
0.85
.;.;.;T
Sift4G
Benign
0.73
.;.;.;T
Polyphen
0.81
.;.;P;.
Vest4
0.38
MutPred
0.40
Gain of disorder (P = 0.0636);Gain of disorder (P = 0.0636);Gain of disorder (P = 0.0636);Gain of disorder (P = 0.0636);
MVP
0.72
MPC
1.1
ClinPred
0.74
D
GERP RS
4.8
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7
Varity_R
0.40
gMVP
0.78

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.030
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

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs1554404461; hg19: chr7-140507818; API