X-153909744-G-T

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_001666.5(ARHGAP4):c.2411C>A(p.Ala804Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000028 in 1,073,209 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples in GnomAD. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. A804A) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 24)
  • Exomes 𝑓: 0.0000028 (0 hom. 0 hem.)
• Consequence: ARHGAP4 NM_001666.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.112

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]

ACMG classification

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=0.027393758).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ARHGAP4	NM_001666.5	c.2411C>A	p.Ala804Asp	missense_variant	19/22	ENST00000350060.10
ARHGAP4	NM_001164741.2	c.2531C>A	p.Ala844Asp	missense_variant	20/23

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ARHGAP4	ENST00000350060.10	c.2411C>A	p.Ala804Asp	missense_variant	19/22	1	NM_001666.5	P2

Frequencies

GnomAD3 genomes Cov.: 24

GnomAD4 exome AF: 0.00000280 AC: 3 AN: 1073209 Hom.: 0 Cov.: 35 AF XY: 0.00 AC XY: 0 AN XY: 346069

Gnomad4 AFR exome AF: 0.0000768

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: 0.0000222

GnomAD4 genome Cov.: 24

Bravo AF: 0.0000227

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 22, 2023

The c.2531C>A (p.A844D) alteration is located in exon 20 (coding exon 20) of the ARHGAP4 gene. This alteration results from a C to A substitution at nucleotide position 2531, causing the alanine (A) at amino acid position 844 to be replaced by an aspartic acid (D). 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	0.11
BayesDel_addAF	Benign	-0.50	T
BayesDel_noAF	Benign	-0.95
Cadd	Benign	0.010
Dann	Benign	0.47
FATHMM_MKL	Benign	0.010	N
LIST_S2	Benign	0.59	T;T;T;T
M_CAP	Benign	0.0080	T
MetaRNN	Benign	0.027	T;T;T;T
MetaSVM	Benign	-1.0	T
MutationTaster	Benign	1.0	N;N;N;N;N
PrimateAI	Benign	0.34	T
PROVEAN	Benign	3.7	N;N;N;N
REVEL	Benign	0.040
Sift	Benign	0.48	T;T;T;T
Sift4G	Benign	0.71	T;T;T;T
Polyphen		0.0040	.;.;B;.
Vest4		0.095
MutPred		0.33		.;.;Loss of catalytic residue at A804 (P = 0.07);.;
MVP		0.14
MPC		0.027
ClinPred		0.017	T
GERP RS		-8.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.090
gMVP		0.38

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: rs1557102318; hg19: chrX-153175198;