NM_001666.5:c.2458G>C

Variant names:

• chrX-153909492-C-G
• NM_001666.5:c.2458G>C

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001666.5(ARHGAP4):​c.2458G>C​(p.Glu820Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 26)
• Consequence: ARHGAP4 NM_001666.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.821
• 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: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.12424454).

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.2458G>C	p.Glu820Gln	missense	Exon 20 of 22	NP_001657.3
	ARHGAP4	NM_001164741.2		c.2578G>C	p.Glu860Gln	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.2458G>C	p.Glu820Gln	missense	Exon 20 of 22	ENSP00000203786.8	P98171-1
	ARHGAP4	ENST00000370028.7	TSL:1	c.2578G>C	p.Glu860Gln	missense	Exon 21 of 23	ENSP00000359045.3	P98171-2
	ARHGAP4	ENST00000968871.1		c.2476G>C	p.Glu826Gln	missense	Exon 20 of 22	ENSP00000638930.1

Frequencies

GnomAD3 genomes Cov.: 26

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 26

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.086
BayesDel_addAF	Benign	-0.47	T
BayesDel_noAF	Benign	-0.91
CADD	Benign	15
DANN	Benign	0.93
DEOGEN2	Benign	0.11	T
FATHMM_MKL	Benign	0.015	N
LIST_S2	Benign	0.82	T
M_CAP	Benign	0.0047	T
MetaRNN	Benign	0.12	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.55	N
PhyloP100		0.82
PrimateAI	Benign	0.43	T
PROVEAN	Benign	-0.99	N
REVEL	Benign	0.029
Sift	Benign	0.11	T
Sift4G	Benign	0.26	T
Polyphen		0.034	B
Vest4		0.18
MutPred		0.098		Gain of glycosylation at S821 (P = 0.0982)
MVP		0.31
MPC		0.023
ClinPred		0.17	T
GERP RS		3.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.14
gMVP		0.44
Mutation Taster		=93/7	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

hg19: chrX-153174946;