NM_001666.5:c.2437G>A

Variant names:

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

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_Strong BS2

The NM_001666.5(ARHGAP4):​c.2437G>A​(p.Ala813Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000994 in 1,207,635 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 2 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. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.0000089 (0 hom., 0 hem., cov: 26)
  • Exomes 𝑓: 0.000010 (0 hom. 2 hem.)
• Consequence: ARHGAP4 NM_001666.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• 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: Benign. The variant received -8 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.037199408).
• BS2: High Hemizygotes in GnomAdExome4 at 2 XL gene

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>A	p.Ala813Thr	missense	Exon 20 of 22	NP_001657.3
	ARHGAP4	NM_001164741.2		c.2557G>A	p.Ala853Thr	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>A	p.Ala813Thr	missense	Exon 20 of 22	ENSP00000203786.8	P98171-1
	ARHGAP4	ENST00000370028.7	TSL:1	c.2557G>A	p.Ala853Thr	missense	Exon 21 of 23	ENSP00000359045.3	P98171-2
	ARHGAP4	ENST00000968871.1		c.2455G>A	p.Ala819Thr	missense	Exon 20 of 22	ENSP00000638930.1

Frequencies

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

Gnomad AFR AF: 0.0000322

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

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

GnomAD2 exomes AF: 0.00000571 AC: 1 AN: 174995 AF XY: 0.00

Gnomad AFR exome AF: 0.0000786

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000100 AC: 11 AN: 1094681 Hom.: 0 Cov.: 33 AF XY: 0.00000554 AC XY: 2 AN XY: 360795

African (AFR) AF: 0.000114 AC: 3 AN: 26337

American (AMR) AF: 0.00 AC: 0 AN: 34825

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19237

East Asian (EAS) AF: 0.00 AC: 0 AN: 30176

South Asian (SAS) AF: 0.00 AC: 0 AN: 53663

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 39657

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4122

European-Non Finnish (NFE) AF: 0.00000833 AC: 7 AN: 840703

Other (OTH) AF: 0.0000218 AC: 1 AN: 45961

GnomAD4 genome AF: 0.00000885 AC: 1 AN: 112954 Hom.: 0 Cov.: 26 AF XY: 0.00 AC XY: 0 AN XY: 35108

African (AFR) AF: 0.0000321 AC: 1 AN: 31158

American (AMR) AF: 0.00 AC: 0 AN: 10806

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 3558

South Asian (SAS) AF: 0.00 AC: 0 AN: 2781

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

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 219

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 53231

Other (OTH) AF: 0.00 AC: 0 AN: 1541

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000189

ESP6500AA AF: 0.000261 AC: 1

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00000824 AC: 1

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	0.066
BayesDel_addAF	Benign	-0.55	T
BayesDel_noAF	Benign	-1.0
CADD	Benign	1.3
DANN	Benign	0.94
DEOGEN2	Benign	0.045	T
FATHMM_MKL	Benign	0.0036	N
LIST_S2	Benign	0.79	T
M_CAP	Benign	0.0023	T
MetaRNN	Benign	0.037	T
MetaSVM	Benign	-0.94	T
MutationAssessor	Benign	0.34	N
PhyloP100		-0.086
PrimateAI	Benign	0.34	T
PROVEAN	Benign	-0.52	N
REVEL	Benign	0.0060
Sift	Benign	0.43	T
Sift4G	Benign	0.57	T
Polyphen		0.13	B
Vest4		0.095
MVP		0.14
MPC		0.025
ClinPred		0.020	T
GERP RS		1.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Varity_R		0.034
gMVP		0.35
Mutation Taster		=95/5	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;