rs143619652

Variant names:

• chrX-153909533-G-A
• rs143619652
• NM_001666.5:c.2417C>T

Variant summary

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

The NM_001666.5(ARHGAP4):​c.2417C>T​(p.Thr806Met) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000424 in 1,203,743 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 17 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. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000035 (0 hom., 2 hem., cov: 25)
  • Exomes 𝑓: 0.000043 (0 hom. 15 hem.)
• Consequence: ARHGAP4 NM_001666.5 missense, splice_region
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.860
• Publications: 1 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=0.06562203).
• BS2: High Hemizygotes in GnomAd4 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.2417C>T	p.Thr806Met	missense splice_region	Exon 20 of 22	NP_001657.3
	ARHGAP4	NM_001164741.2		c.2537C>T	p.Thr846Met	missense splice_region	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.2417C>T	p.Thr806Met	missense splice_region	Exon 20 of 22	ENSP00000203786.8	P98171-1
	ARHGAP4	ENST00000370028.7	TSL:1	c.2537C>T	p.Thr846Met	missense splice_region	Exon 21 of 23	ENSP00000359045.3	P98171-2
	ARHGAP4	ENST00000968871.1		c.2435C>T	p.Thr812Met	missense splice_region	Exon 20 of 22	ENSP00000638930.1

Frequencies

GnomAD3 genomes AF: 0.0000355 AC: 4 AN: 112709 Hom.: 0 Cov.: 25

Gnomad AFR AF: 0.0000322

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000281

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000376

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000236 AC: 4 AN: 169222 AF XY: 0.0000352

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.000149

Gnomad EAS exome AF: 0.0000756

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000268

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000431 AC: 47 AN: 1091034 Hom.: 0 Cov.: 33 AF XY: 0.0000420 AC XY: 15 AN XY: 357546

African (AFR) AF: 0.00 AC: 0 AN: 26274

American (AMR) AF: 0.00 AC: 0 AN: 34546

Ashkenazi Jewish (ASJ) AF: 0.000158 AC: 3 AN: 19033

East Asian (EAS) AF: 0.00 AC: 0 AN: 30135

South Asian (SAS) AF: 0.00 AC: 0 AN: 52891

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 39435

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4087

European-Non Finnish (NFE) AF: 0.0000477 AC: 40 AN: 838844

Other (OTH) AF: 0.0000874 AC: 4 AN: 45789

GnomAD4 genome AF: 0.0000355 AC: 4 AN: 112709 Hom.: 0 Cov.: 25 AF XY: 0.0000574 AC XY: 2 AN XY: 34857

African (AFR) AF: 0.0000322 AC: 1 AN: 31019

American (AMR) AF: 0.00 AC: 0 AN: 10768

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2654

East Asian (EAS) AF: 0.000281 AC: 1 AN: 3565

South Asian (SAS) AF: 0.00 AC: 0 AN: 2776

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6287

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 239

European-Non Finnish (NFE) AF: 0.0000376 AC: 2 AN: 53192

Other (OTH) AF: 0.00 AC: 0 AN: 1524

Alfa AF: 0.000182 Hom.: 1

Bravo AF: 0.0000491

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000149 AC: 1

ExAC AF: 0.0000248 AC: 3

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	0.071
BayesDel_addAF	Benign	-0.47	T
BayesDel_noAF	Benign	-0.92
CADD	Benign	6.8
DANN	Benign	0.94
DEOGEN2	Benign	0.071	T
FATHMM_MKL	Benign	0.042	N
LIST_S2	Benign	0.78	T
M_CAP	Benign	0.0076	T
MetaRNN	Benign	0.066	T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	0.34	N
PhyloP100		-0.86
PrimateAI	Benign	0.38	T
PROVEAN	Benign	-0.76	N
REVEL	Benign	0.022
Sift	Benign	0.074	T
Sift4G	Benign	0.13	T
Polyphen		0.45	B
Vest4		0.17
MVP		0.17
MPC		0.033
ClinPred		0.025	T
GERP RS		1.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Varity_R		0.021
gMVP		0.35
Mutation Taster		=98/2	polymorphism

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

Other links and lift over

dbSNP: rs143619652; hg19: chrX-153174987;