Variant X-47566737-A-G details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_001654.5(ARAF):c.656A>G(p.His219Arg) variant causes a missense change. The variant allele was found at a frequency of 0.000000913 in 1,095,730 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples in GnomAD. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 22)

Exomes 𝑓: 9.1e-7 ( 0 hom. 0 hem. )

Consequence

ARAF
NM_001654.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 7.01

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 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ARAF	NM_001654.5 link	c.656A>G	p.His219Arg	missense_variant	Exon 7 of 16	ENST00000377045.9	NP_001645.1	P10398-1A0A024R178
ARAF	NM_001256196.2 link	c.665A>G	p.His222Arg	missense_variant	Exon 7 of 16		NP_001243125.1	P10398Q96II5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ARAF	ENST00000377045.9 link	c.656A>G	p.His219Arg	missense_variant	Exon 7 of 16	1	NM_001654.5	ENSP00000366244.4		P10398-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000562

AC:

AN:

178011

Hom.:

AF XY:

0.00

AC XY:

AN XY:

63021

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:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.000228

GnomAD4 exome

AF:

9.13e-7

AC:

AN:

1095730

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

361428

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:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.0000217

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

May 23, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.656A>G (p.H219R) alteration is located in exon 7 (coding exon 6) of the ARAF gene. This alteration results from a A to G substitution at nucleotide position 656, causing the histidine (H) at amino acid position 219 to be replaced by an arginine (R). 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

Pathogenic

0.70

BayesDel_addAF

Pathogenic

0.31

BayesDel_noAF

Pathogenic

0.20

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Benign

0.36

T;D

FATHMM_MKL

Uncertain

0.97

LIST_S2

Uncertain

0.91

D;D

M_CAP

Pathogenic

0.43

MetaRNN

Uncertain

0.49

T;T

MetaSVM

Uncertain

-0.19

MutationAssessor

Uncertain

2.7

.;M

PrimateAI

Uncertain

0.77

PROVEAN

Uncertain

-3.9

.;D

REVEL

Uncertain

0.59

Sift

Benign

0.042

.;D

Sift4G

Uncertain

0.059

T;T

Polyphen

0.82

.;P

Vest4

0.52

MutPred

0.23

.;Gain of MoRF binding (P = 0.0083);

MVP

0.95

MPC

0.20

ClinPred

0.52

GERP RS

5.4

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.75

gMVP

0.67

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.060

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