dbSNP rs376883664: ARHGAP4:p.Ala813Ser (chrX-153909513-C-A) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_001666.5(ARHGAP4):c.2437G>T(p.Ala813Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000886 in 112,900 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. 14/20 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 0.0000089 ( 0 hom., 1 hem., cov: 26)

Consequence

ARHGAP4
NM_001666.5 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.0860

Variant links:

Genes affected

ARHGAP4 (HGNC:674): (Rho GTPase activating protein 4) This gene encodes a member of the rhoGAP family of proteins which play a role in the regulation of small GTP-binding proteins belonging to the RAS superfamily. The protein encoded by the orthologous gene in rat is localized to the Golgi complex and can redistribute to microtubules. The rat protein stimulates the activity of some Rho GTPases in vitro. Genomic deletions of this gene and a neighboring gene have been found in patients with nephrogenic diabetes insipidus. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Sep 2009]

ARHGAP4 links:

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ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.042835772).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ARHGAP4	NM_001666.5 link	c.2437G>T	p.Ala813Ser	missense_variant	Exon 20 of 22	ENST00000350060.10	NP_001657.3	P98171-1
ARHGAP4	NM_001164741.2 link	c.2557G>T	p.Ala853Ser	missense_variant	Exon 21 of 23		NP_001158213.1	P98171-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ARHGAP4	ENST00000350060.10 link	c.2437G>T	p.Ala813Ser	missense_variant	Exon 20 of 22	1	NM_001666.5	ENSP00000203786.8		P98171-1

Frequencies

GnomAD3 genomes

AF:

0.00000886

AC:

AN:

112900

Hom.:

Cov.:

AF XY:

0.0000285

AC XY:

AN XY:

35044

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000927

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD4 exome

Cov.:

GnomAD4 genome

AF:

0.00000886

AC:

AN:

112900

Hom.:

Cov.:

AF XY:

0.0000285

AC XY:

AN XY:

35044

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.0000927

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.073

BayesDel_addAF

Benign

-0.48

BayesDel_noAF

Benign

-0.93

CADD

Benign

0.57

DANN

Benign

0.94

DEOGEN2

Benign

0.035

.;.;T;T

FATHMM_MKL

Benign

0.016

LIST_S2

Benign

0.63

T;T;T;T

M_CAP

Benign

0.0022

MetaRNN

Benign

0.043

T;T;T;T

MetaSVM

Benign

-0.95

MutationAssessor

Benign

0.0

.;.;N;.

PrimateAI

Benign

0.33

PROVEAN

Benign

0.29

N;N;N;N

REVEL

Benign

0.0070

Sift

Benign

1.0

T;T;T;T

Sift4G

Benign

0.73

T;T;T;T

Polyphen

0.0020

.;.;B;.

Vest4

0.079

MutPred

0.28

.;.;Gain of glycosylation at A813 (P = 0.0017);.;

MVP

0.17

MPC

0.022

ClinPred

0.052

GERP RS

1.3

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.0

Varity_R

0.049

gMVP

0.32

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

Computational scores

Splicing

Publications

LitVar

Other links and lift over