Variant X-47565291-A-T details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_001654.5(ARAF):c.498A>T(p.Arg166Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000179 in 111,697 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 1 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000018 ( 0 hom., 1 hem., cov: 23)

Consequence

ARAF
NM_001654.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.113

Variant links:

Genes affected

ARAF (HGNC:646): (A-Raf proto-oncogene, serine/threonine kinase) Enables protein serine/threonine kinase activity. Involved in negative regulation of apoptotic process; regulation of TOR signaling; and regulation of cellular protein metabolic process. Predicted to be active in cytosol and mitochondrion. Biomarker of high grade glioma. [provided by Alliance of Genome Resources, Apr 2022]

ARAF links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.12927607).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
ARAF	NM_001654.5 linkuse as main transcript	c.498A>T	p.Arg166Ser	missense_variant	6/16	ENST00000377045.9
ARAF	NM_001256196.2 linkuse as main transcript	c.507A>T	p.Arg169Ser	missense_variant	6/16
ARAF	NM_001256197.2 linkuse as main transcript	c.498A>T	p.Arg166Ser	missense_variant	6/6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ARAF	ENST00000377045.9 linkuse as main transcript	c.498A>T	p.Arg166Ser	missense_variant	6/16	1	NM_001654.5	P1	P10398-1
ARAF	ENST00000377039.2 linkuse as main transcript	c.498A>T	p.Arg166Ser	missense_variant	6/6	2			P10398-2

Frequencies

GnomAD3 genomes

AF:

0.0000179

AC:

AN:

111697

Hom.:

Cov.:

AF XY:

0.0000295

AC XY:

AN XY:

33863

show subpopulations

Gnomad AFR

AF:

0.0000652

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00000546

AC:

AN:

183314

Hom.:

AF XY:

0.00

AC XY:

AN XY:

67784

show subpopulations

Gnomad AFR exome

AF:

0.0000760

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

Cov.:

GnomAD4 genome

AF:

0.0000179

AC:

AN:

111697

Hom.:

Cov.:

AF XY:

0.0000295

AC XY:

AN XY:

33863

show subpopulations

Gnomad4 AFR

AF:

0.0000652

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.00000378

ESP6500AA

AF:

0.000261

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.00000824

AC:

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 submitter

clinical testing

Ambry Genetics

Mar 20, 2023

The c.498A>T (p.R166S) alteration is located in exon 6 (coding exon 5) of the ARAF gene. This alteration results from a A to T substitution at nucleotide position 498, causing the arginine (R) at amino acid position 166 to be replaced by a serine (S). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.12

BayesDel_addAF

Uncertain

0.092

BayesDel_noAF

Benign

-0.11

CADD

Benign

8.4

DANN

Benign

0.96

DEOGEN2

Benign

0.22

T;T;.

FATHMM_MKL

Benign

0.39

LIST_S2

Benign

0.86

D;T;D

M_CAP

Uncertain

0.12

MetaRNN

Benign

0.13

T;T;T

MetaSVM

Benign

-0.54

MutationAssessor

Benign

0.41

.;N;N

MutationTaster

Benign

0.88

N;N;N

PrimateAI

Benign

0.34

PROVEAN

Benign

0.86

.;N;N

REVEL

Uncertain

0.43

Sift

Benign

0.74

.;T;D

Sift4G

Benign

0.77

T;T;T

Polyphen

0.0020

.;B;.

Vest4

0.54

MutPred

0.18

.;Gain of phosphorylation at R166 (P = 0.0302);Gain of phosphorylation at R166 (P = 0.0302);

MVP

0.91

MPC

0.084

ClinPred

0.063

GERP RS

0.29

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.13

gMVP

0.60

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

Publications

LitVar

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

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over