Variant X-47566652-C-T details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_StrongBS2

The NM_001654.5(ARAF):c.571C>T(p.His191Tyr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000827 in 1,172,409 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 33 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000063 ( 0 hom., 2 hem., cov: 22)

Exomes 𝑓: 0.000085 ( 0 hom. 31 hem. )

Consequence

ARAF
NM_001654.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.14

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 Benign. Variant got -8 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.033817887).

BS2

High Hemizygotes in GnomAd4 at 2 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ARAF	NM_001654.5 linkuse as main transcript	c.571C>T	p.His191Tyr	missense_variant	7/16	ENST00000377045.9
ARAF	NM_001256196.2 linkuse as main transcript	c.580C>T	p.His194Tyr	missense_variant	7/16

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ARAF	ENST00000377045.9 linkuse as main transcript	c.571C>T	p.His191Tyr	missense_variant	7/16	1	NM_001654.5	P1	P10398-1

Frequencies

GnomAD3 genomes

AF:

0.0000630

AC:

AN:

111102

Hom.:

Cov.:

AF XY:

0.0000601

AC XY:

AN XY:

33276

show subpopulations

Gnomad AFR

AF:

0.0000329

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.000757

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000756

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000479

AC:

AN:

146259

Hom.:

AF XY:

0.0000890

AC XY:

AN XY:

44959

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.000745

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000608

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000848

AC:

AN:

1061307

Hom.:

Cov.:

AF XY:

0.0000907

AC XY:

AN XY:

341781

show subpopulations

Gnomad4 AFR exome

AF:

0.0000781

Gnomad4 AMR exome

AF:

0.0000638

Gnomad4 ASJ exome

AF:

0.000606

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000766

Gnomad4 OTH exome

AF:

0.0000900

GnomAD4 genome

AF:

0.0000630

AC:

AN:

111102

Hom.:

Cov.:

AF XY:

0.0000601

AC XY:

AN XY:

33276

show subpopulations

Gnomad4 AFR

AF:

0.0000329

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.000757

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000756

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000131

Hom.:

Bravo

AF:

0.0000718

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000346

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000149

AC:

ExAC

AF:

0.0000664

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

Apr 06, 2023

The c.571C>T (p.H191Y) alteration is located in exon 7 (coding exon 6) of the ARAF gene. This alteration results from a C to T substitution at nucleotide position 571, causing the histidine (H) at amino acid position 191 to be replaced by a tyrosine (Y). 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

0.076

BayesDel_addAF

Benign

-0.30

BayesDel_noAF

Benign

-0.59

CADD

Benign

DANN

Benign

0.33

DEOGEN2

Benign

0.23

T;T

FATHMM_MKL

Benign

0.76

LIST_S2

Benign

0.83

T;T

M_CAP

Benign

0.020

MetaRNN

Benign

0.034

T;T

MetaSVM

Benign

-0.90

MutationAssessor

Benign

1.1

.;L

MutationTaster

Benign

1.0

D;N

PrimateAI

Uncertain

0.54

PROVEAN

Benign

-0.19

.;N

REVEL

Benign

0.059

Sift

Benign

0.94

.;T

Sift4G

Benign

1.0

T;T

Polyphen

0.0

.;B

Vest4

0.14

MVP

0.61

MPC

0.089

ClinPred

0.019

GERP RS

2.4

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.072

gMVP

0.40

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