X-153907884-A-G

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_001666.5(ARHGAP4):c.2686T>C(p.Ser896Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000085 in 941,109 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 4 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. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 25)
  • Exomes 𝑓: 0.0000085 (0 hom. 4 hem.)
• Consequence: ARHGAP4 NM_001666.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -3.54

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.

• BP4: Computational evidence support a benign effect (MetaRNN=0.07251239).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ARHGAP4	NM_001666.5	c.2686T>C	p.Ser896Pro	missense_variant	22/22	ENST00000350060.10
ARHGAP4	NM_001164741.2	c.2806T>C	p.Ser936Pro	missense_variant	23/23

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ARHGAP4	ENST00000350060.10	c.2686T>C	p.Ser896Pro	missense_variant	22/22	1	NM_001666.5	P2

Frequencies

GnomAD3 genomes Cov.: 25

GnomAD4 exome AF: 0.00000850 AC: 8 AN: 941109 Hom.: 0 Cov.: 30 AF XY: 0.0000136 AC XY: 4 AN XY: 293227

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: 0.0000105

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 25

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

Apr 07, 2022

The c.2806T>C (p.S936P) alteration is located in exon 23 (coding exon 23) of the ARHGAP4 gene. This alteration results from a T to C substitution at nucleotide position 2806, causing the serine (S) at amino acid position 936 to be replaced by a proline (P). 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	0.054
BayesDel_addAF	Benign	-0.59	T
BayesDel_noAF	Benign	-1.1
Cadd	Benign	0.064
Dann	Benign	0.61
FATHMM_MKL	Benign	0.035	N
LIST_S2	Benign	0.54	T;T;T;T
M_CAP	Benign	0.0035	T
MetaRNN	Benign	0.073	T;T;T;T
MetaSVM	Benign	-0.95	T
MutationTaster	Benign	1.0	N;N;N;N;N
PrimateAI	Benign	0.41	T
PROVEAN	Benign	-0.82	N;N;N;N
REVEL	Benign	0.016
Sift	Benign	0.14	T;T;T;T
Sift4G	Benign	0.28	T;T;T;T
Polyphen		0.0	.;.;B;.
Vest4		0.055
MutPred		0.11		.;.;Loss of phosphorylation at S896 (P = 0.0107);.;
MVP		0.093
MPC		0.025
ClinPred		0.29	T
GERP RS		-5.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Varity_R		0.098
gMVP		0.27

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: rs1557101623; hg19: chrX-153173338;