Variant X-47565335-C-A details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 2P and 8B. PM1BP4_StrongBS2

The NM_001654.5(ARAF):c.542C>A(p.Thr181Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00111 in 1,208,966 control chromosomes in the GnomAD database, including 1 homozygotes. There are 414 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 0.0012 ( 1 hom., 49 hem., cov: 23)

Exomes 𝑓: 0.0011 ( 0 hom. 365 hem. )

Consequence

ARAF
NM_001654.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.96

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 Likely_benign. Variant got -6 ACMG points.

PM1

In a modified_residue Phosphothreonine (size 0) in uniprot entity ARAF_HUMAN

BP4

Computational evidence support a benign effect (MetaRNN=0.017808765).

BS2

High Hemizygotes in GnomAd4 at 49 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
ARAF	NM_001654.5 linkuse as main transcript	c.542C>A	p.Thr181Asn	missense_variant	6/16	ENST00000377045.9
ARAF	NM_001256196.2 linkuse as main transcript	c.551C>A	p.Thr184Asn	missense_variant	6/16
ARAF	NM_001256197.2 linkuse as main transcript	c.542C>A	p.Thr181Asn	missense_variant	6/6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ARAF	ENST00000377045.9 linkuse as main transcript	c.542C>A	p.Thr181Asn	missense_variant	6/16	1	NM_001654.5	P1	P10398-1
ARAF	ENST00000377039.2 linkuse as main transcript	c.542C>A	p.Thr181Asn	missense_variant	6/6	2			P10398-2

Frequencies

GnomAD3 genomes

AF:

0.00123

AC:

138

AN:

112005

Hom.:

Cov.:

AF XY:

0.00143

AC XY:

AN XY:

34167

show subpopulations

Gnomad AFR

AF:

0.000228

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00683

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:

0.00105

Gnomad OTH

AF:

0.00198

GnomAD3 exomes

AF:

0.000783

AC:

143

AN:

182592

Hom.:

AF XY:

0.000730

AC XY:

AN XY:

67138

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00198

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:

0.000981

Gnomad OTH exome

AF:

0.00200

GnomAD4 exome

AF:

0.00110

AC:

1209

AN:

1096908

Hom.:

Cov.:

AF XY:

0.00101

AC XY:

365

AN XY:

362312

show subpopulations

Gnomad4 AFR exome

AF:

0.0000758

Gnomad4 AMR exome

AF:

0.00179

Gnomad4 ASJ exome

AF:

0.000207

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.0000494

Gnomad4 NFE exome

AF:

0.00130

Gnomad4 OTH exome

AF:

0.000890

GnomAD4 genome

AF:

0.00123

AC:

138

AN:

112058

Hom.:

Cov.:

AF XY:

0.00143

AC XY:

AN XY:

34230

show subpopulations

Gnomad4 AFR

AF:

0.000227

Gnomad4 AMR

AF:

0.00682

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00105

Gnomad4 OTH

AF:

0.00196

Alfa

AF:

0.000680

Hom.:

Bravo

AF:

0.00139

ESP6500AA

AF:

0.000522

AC:

ESP6500EA

AF:

0.000892

AC:

ExAC

AF:

0.000659

AC:

EpiCase

AF:

0.000819

EpiControl

AF:

0.00137

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 23, 2024

The c.542C>A (p.T181N) alteration is located in exon 6 (coding exon 5) of the ARAF gene. This alteration results from a C to A substitution at nucleotide position 542, causing the threonine (T) at amino acid position 181 to be replaced by an asparagine (N). 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

0.096

BayesDel_addAF

Benign

-0.19

BayesDel_noAF

Uncertain

-0.050

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.28

T;D;.

FATHMM_MKL

Uncertain

0.79

LIST_S2

Benign

0.82

T;T;T

M_CAP

Pathogenic

0.32

MetaRNN

Benign

0.018

T;T;T

MetaSVM

Uncertain

0.66

MutationAssessor

Uncertain

2.3

.;M;M

MutationTaster

Benign

0.54

N;N;N

PrimateAI

Uncertain

0.55

PROVEAN

Benign

-0.97

.;N;N

REVEL

Uncertain

0.33

Sift

Benign

0.16

.;T;D

Sift4G

Benign

0.28

T;T;D

Polyphen

0.75

.;P;.

Vest4

0.53

MVP

0.91

MPC

0.16

ClinPred

0.056

GERP RS

4.6

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.0

Varity_R

0.28

gMVP

0.71

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

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