X-153907748-G-A

Variant names:

• chrX-153907748-G-A
• rs186581498
• NM_001666.5:c.2822C>T

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP4_Strong BP6_Moderate BS2

The NM_001666.5(ARHGAP4):​c.2822C>T​(p.Thr941Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000195 in 1,003,083 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 54 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 12/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.00028 (0 hom., 11 hem., cov: 24)
  • Exomes 𝑓: 0.00018 (0 hom. 43 hem.)
• Consequence: ARHGAP4 NM_001666.5 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.210

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]

ENSG00000284987 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -10 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0033698976).
• BP6: Variant X-153907748-G-A is Benign according to our data. Variant chrX-153907748-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 2661746.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chrX-153907748-G-A is described in Lovd as [Likely_benign].
• BS2: High Hemizygotes in GnomAd4 at 11 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ARHGAP4	NM_001666.5	c.2822C>T	p.Thr941Met	missense_variant	Exon 22 of 22	ENST00000350060.10	NP_001657.3
ARHGAP4	NM_001164741.2	c.2942C>T	p.Thr981Met	missense_variant	Exon 23 of 23		NP_001158213.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ARHGAP4	ENST00000350060.10	c.2822C>T	p.Thr941Met	missense_variant	Exon 22 of 22	1	NM_001666.5	ENSP00000203786.8
ENSG00000284987	ENST00000646191.1	n.96+1322C>T		intron_variant	Intron 1 of 4			ENSP00000493873.1

Frequencies

GnomAD3 genomes AF: 0.000284 AC: 32 AN: 112829 Hom.: 0 Cov.: 24 AF XY: 0.000314 AC XY: 11 AN XY: 34989

Gnomad AFR AF: 0.0000321

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00817

Gnomad SAS AF: 0.000361

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.000653

GnomAD3 exomes AF: 0.000730 AC: 58 AN: 79449 Hom.: 0 AF XY: 0.000362 AC XY: 10 AN XY: 27625

Gnomad AFR exome AF: 0.000158

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00931

Gnomad SAS exome AF: 0.000567

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000184 AC: 164 AN: 890205 Hom.: 0 Cov.: 21 AF XY: 0.000161 AC XY: 43 AN XY: 267343

Gnomad4 AFR exome AF: 0.0000514

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00556

Gnomad4 SAS exome AF: 0.000459

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000550

Gnomad4 OTH exome AF: 0.000414

GnomAD4 genome AF: 0.000283 AC: 32 AN: 112878 Hom.: 0 Cov.: 24 AF XY: 0.000314 AC XY: 11 AN XY: 35048

Gnomad4 AFR AF: 0.0000321

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00820

Gnomad4 SAS AF: 0.000362

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.000645

Alfa AF: 0.000214 Hom.: 1

Bravo AF: 0.000627

ESP6500AA AF: 0.000275 AC: 1

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000781 AC: 87

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Sep 01, 2023

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

ARHGAP4: BP4, BS2 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.081
BayesDel_addAF	Benign	-0.86	T
BayesDel_noAF	Benign	-1.0
CADD	Benign	6.9
DANN	Uncertain	0.99
DEOGEN2	Benign	0.081	.;.;T;T
FATHMM_MKL	Benign	0.042	N
LIST_S2	Benign	0.62	T;T;T;T
MetaRNN	Benign	0.0034	T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.0	.;.;N;.
PrimateAI	Benign	0.37	T
PROVEAN	Benign	-0.92	N;N;N;N
REVEL	Benign	0.20
Sift	Uncertain	0.0010	D;D;D;D
Sift4G	Uncertain	0.010	D;D;D;D
Polyphen		0.77	.;.;P;.
Vest4		0.13
MVP		0.14
MPC		0.027
ClinPred		0.032	T
GERP RS		-2.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.035
gMVP		0.37

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

Other links and lift over

dbSNP: rs186581498; hg19: chrX-153173202;