X-153909513-C-A

Variant names:

• chrX-153909513-C-A
• rs376883664
• NM_001666.5:c.2437G>T

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_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. 15/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A813T) has been classified as Uncertain significance.

• Frequency: Genomes: 𝑓 0.0000089 (0 hom., 1 hem., cov: 26)
• Consequence: ARHGAP4 NM_001666.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0860
• Publications: 0 publications found

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 Gene-Disease associations (from GenCC):

• intellectual disability

  Inheritance: XL Classification: LIMITED Submitted by: Ambry Genetics

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.042835772).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001666.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ARHGAP4	NM_001666.5	MANE Select	c.2437G>T	p.Ala813Ser	missense	Exon 20 of 22	NP_001657.3
	ARHGAP4	NM_001164741.2		c.2557G>T	p.Ala853Ser	missense	Exon 21 of 23	NP_001158213.1	P98171-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ARHGAP4	ENST00000350060.10	TSL:1 MANE Select	c.2437G>T	p.Ala813Ser	missense	Exon 20 of 22	ENSP00000203786.8	P98171-1
	ARHGAP4	ENST00000370028.7	TSL:1	c.2557G>T	p.Ala853Ser	missense	Exon 21 of 23	ENSP00000359045.3	P98171-2
	ARHGAP4	ENST00000968871.1		c.2455G>T	p.Ala819Ser	missense	Exon 20 of 22	ENSP00000638930.1

Frequencies

GnomAD3 genomes AF: 0.00000886 AC: 1 AN: 112900 Hom.: 0 Cov.: 26

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.: 33

GnomAD4 genome AF: 0.00000886 AC: 1 AN: 112900 Hom.: 0 Cov.: 26 AF XY: 0.0000285 AC XY: 1 AN XY: 35044

African (AFR) AF: 0.00 AC: 0 AN: 31089

American (AMR) AF: 0.0000927 AC: 1 AN: 10793

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2655

East Asian (EAS) AF: 0.00 AC: 0 AN: 3569

South Asian (SAS) AF: 0.00 AC: 0 AN: 2789

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6316

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 240

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 53238

Other (OTH) AF: 0.00 AC: 0 AN: 1522

Alfa AF: 0.00 Hom.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.073
BayesDel_addAF	Benign	-0.48	T
BayesDel_noAF	Benign	-0.93
CADD	Benign	0.57
DANN	Benign	0.94
DEOGEN2	Benign	0.035	T
FATHMM_MKL	Benign	0.016	N
LIST_S2	Benign	0.63	T
M_CAP	Benign	0.0022	T
MetaRNN	Benign	0.043	T
MetaSVM	Benign	-0.95	T
MutationAssessor	Benign	0.0	N
PhyloP100		-0.086
PrimateAI	Benign	0.33	T
PROVEAN	Benign	0.29	N
REVEL	Benign	0.0070
Sift	Benign	1.0	T
Sift4G	Benign	0.73	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	T
GERP RS		1.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Varity_R		0.049
gMVP		0.32
Mutation Taster		=96/4	polymorphism

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

Other links and lift over

dbSNP: rs376883664; hg19: chrX-153174967;