Genetic Variant ARAF:p.Asn150Thr (chrX-47565130-A-C) – ACMG Classification: Benign (-8 pts)

Variant summary

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

The NM_001654.5(ARAF):c.449A>C(p.Asn150Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000271 in 110,541 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 2 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.000027 ( 0 hom., 2 hem., cov: 23)

Exomes 𝑓: 0.000021 ( 0 hom. 7 hem. )

Failed GnomAD Quality Control

Consequence

ARAF
NM_001654.5 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.832

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=0.064331084).

BS2

High Hemizygotes in GnomAd4 at 2 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ARAF	NM_001654.5 link	c.449A>C	p.Asn150Thr	missense_variant	Exon 5 of 16	ENST00000377045.9	NP_001645.1	P10398-1A0A024R178
ARAF	NM_001256196.2 link	c.449A>C	p.Asn150Thr	missense_variant	Exon 5 of 16		NP_001243125.1	P10398Q96II5
ARAF	NM_001256197.2 link	c.449A>C	p.Asn150Thr	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.449A>C	p.Asn150Thr	missense_variant	Exon 5 of 16	1	NM_001654.5	ENSP00000366244.4	P10398-1
ARAF	ENST00000377039.2 link	c.449A>C	p.Asn150Thr	missense_variant	Exon 5 of 6	2		ENSP00000366238.1	P10398-2
ARAF	ENST00000489496.1 link	n.369A>C		non_coding_transcript_exon_variant	Exon 4 of 4	5

Frequencies

GnomAD3 genomes

AF:

0.0000272

AC:

AN:

110479

Hom.:

Cov.:

AF XY:

0.0000604

AC XY:

AN XY:

33109

show subpopulations

Gnomad AFR

AF:

0.0000329

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:

0.0000380

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000166

AC:

AN:

180545

Hom.:

AF XY:

0.0000153

AC XY:

AN XY:

65415

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:

0.0000374

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.0000213

AC:

AN:

1081639

Hom.:

Cov.:

AF XY:

0.0000199

AC XY:

AN XY:

351989

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:

0.0000278

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000271

AC:

AN:

110541

Hom.:

Cov.:

AF XY:

0.0000603

AC XY:

AN XY:

33175

show subpopulations

Gnomad4 AFR

AF:

0.0000328

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:

0.0000380

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000844

Hom.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.072

BayesDel_addAF

Benign

-0.24

BayesDel_noAF

Benign

-0.47

CADD

Benign

9.8

DANN

Benign

0.90

DEOGEN2

Benign

0.22

T;T;.

FATHMM_MKL

Benign

0.73

LIST_S2

Benign

0.34

T;T;T

M_CAP

Benign

0.057

MetaRNN

Benign

0.064

T;T;T

MetaSVM

Benign

-0.64

MutationAssessor

Benign

0.76

.;N;N

PrimateAI

Benign

0.40

PROVEAN

Benign

0.80

N;N;N

REVEL

Benign

0.15

Sift

Benign

0.63

T;T;T

Sift4G

Benign

0.57

T;T;T

Polyphen

0.0

.;B;.

Vest4

0.19

MutPred

0.31

Gain of glycosylation at N150 (P = 0.0373);Gain of glycosylation at N150 (P = 0.0373);Gain of glycosylation at N150 (P = 0.0373);

MVP

0.59

MPC

0.076

ClinPred

0.030

GERP RS

0.79

Varity_R

0.039

gMVP

0.57

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.050

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

Computational scores

Splicing

Publications

LitVar

Other links and lift over