Variant X-47565132-C-T details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_ModerateBS2

The NM_001654.5(ARAF):c.451C>T(p.Arg151Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000488 in 1,209,082 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 17 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000027 ( 0 hom., 0 hem., cov: 23)

Exomes 𝑓: 0.000051 ( 0 hom. 17 hem. )

Consequence

ARAF
NM_001654.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.68

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -6 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.1976668).

BS2

High Hemizygotes in GnomAdExome4 at 17 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ARAF	NM_001654.5 link	c.451C>T	p.Arg151Cys	missense_variant	Exon 5 of 16	ENST00000377045.9	NP_001645.1	P10398-1A0A024R178
ARAF	NM_001256196.2 link	c.451C>T	p.Arg151Cys	missense_variant	Exon 5 of 16		NP_001243125.1	P10398Q96II5
ARAF	NM_001256197.2 link	c.451C>T	p.Arg151Cys	missense_variant	Exon 5 of 6		NP_001243126.1	P10398-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
ARAF	ENST00000377045.9 link	c.451C>T	p.Arg151Cys	missense_variant	Exon 5 of 16	1	NM_001654.5	ENSP00000366244.4	P10398-1
ARAF	ENST00000377039.2 link	c.451C>T	p.Arg151Cys	missense_variant	Exon 5 of 6	2		ENSP00000366238.1	P10398-2
ARAF	ENST00000489496.1 link	n.371C>T		non_coding_transcript_exon_variant	Exon 4 of 4	5

Frequencies

GnomAD3 genomes

AF:

0.0000268

AC:

AN:

111735

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

33919

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:

0.0000189

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000388

AC:

AN:

180262

Hom.:

AF XY:

0.0000307

AC XY:

AN XY:

65126

show subpopulations

Gnomad AFR exome

AF:

0.000154

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000160

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000250

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000510

AC:

AN:

1097347

Hom.:

Cov.:

AF XY:

0.0000469

AC XY:

AN XY:

362737

show subpopulations

Gnomad4 AFR exome

AF:

0.0000379

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000315

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000440

Gnomad4 OTH exome

AF:

0.0000217

GnomAD4 genome

AF:

0.0000268

AC:

AN:

111735

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

33919

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:

0.0000189

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000142

Hom.:

Bravo

AF:

0.0000416

ExAC

AF:

0.0000412

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Jan 24, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.451C>T (p.R151C) alteration is located in exon 5 (coding exon 4) of the ARAF gene. This alteration results from a C to T substitution at nucleotide position 451, causing the arginine (R) at amino acid position 151 to be replaced by a cysteine (C). 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

0.085

BayesDel_addAF

Benign

-0.090

BayesDel_noAF

Benign

-0.10

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Benign

0.30

T;D;.

FATHMM_MKL

Uncertain

0.86

LIST_S2

Benign

0.85

T;T;T

M_CAP

Pathogenic

0.36

MetaRNN

Benign

0.20

T;T;T

MetaSVM

Uncertain

0.36

MutationAssessor

Uncertain

2.4

.;M;M

PrimateAI

Benign

0.26

PROVEAN

Benign

-2.0

N;N;N

REVEL

Uncertain

0.43

Sift

Benign

0.053

T;T;T

Sift4G

Benign

0.20

T;T;D

Polyphen

1.0

.;D;.

Vest4

0.17

MVP

0.84

MPC

0.32

ClinPred

0.21

GERP RS

2.4

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.11

gMVP

0.81

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.

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