Variant X-47567236-C-G 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.880C>G(p.Leu294Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000273 in 1,098,117 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. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 22)

Exomes 𝑓: 0.0000027 ( 0 hom. 1 hem. )

Consequence

ARAF
NM_001654.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.53

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=0.18663931).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ARAF	NM_001654.5 linkuse as main transcript	c.880C>G	p.Leu294Val	missense_variant	10/16	ENST00000377045.9
ARAF	NM_001256196.2 linkuse as main transcript	c.889C>G	p.Leu297Val	missense_variant	10/16

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ARAF	ENST00000377045.9 linkuse as main transcript	c.880C>G	p.Leu294Val	missense_variant	10/16	1	NM_001654.5	P1	P10398-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000547

AC:

AN:

182837

Hom.:

AF XY:

0.00

AC XY:

AN XY:

67399

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000525

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000273

AC:

AN:

1098117

Hom.:

Cov.:

AF XY:

0.00000275

AC XY:

AN XY:

363475

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000554

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

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 09, 2024

The c.880C>G (p.L294V) alteration is located in exon 10 (coding exon 9) of the ARAF gene. This alteration results from a C to G substitution at nucleotide position 880, causing the leucine (L) at amino acid position 294 to be replaced by a valine (V). 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

0.094

BayesDel_addAF

Benign

-0.24

BayesDel_noAF

Benign

-0.44

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.31

T;T

FATHMM_MKL

Uncertain

0.94

LIST_S2

Uncertain

0.89

D;D

M_CAP

Uncertain

0.11

MetaRNN

Benign

0.19

T;T

MetaSVM

Benign

-0.69

MutationAssessor

Uncertain

2.3

.;M

MutationTaster

Benign

1.0

D;N

PrimateAI

Uncertain

0.62

PROVEAN

Benign

-1.6

.;N

REVEL

Benign

0.12

Sift

Benign

0.091

.;T

Sift4G

Benign

0.53

T;T

Polyphen

0.44

.;B

Vest4

0.16

MutPred

0.24

.;Gain of MoRF binding (P = 0.0968);

MVP

0.84

MPC

0.25

ClinPred

0.34

GERP RS

3.1

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.27

gMVP

0.15

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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