rs149873165

Variant names:

• chrX-153907904-C-A
• rs149873165
• NM_001666.5:c.2666G>T

Your query was ambiguous. Multiple possible variants found:

• chrX-153907904-C-A
• chrX-153907904-C-T

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4 BS2

The NM_001666.5(ARHGAP4):​c.2666G>T​(p.Arg889Leu) variant causes a missense change. The variant allele was found at a frequency of 0.00000527 in 948,025 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. 12/21 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. R889P) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 25)
  • Exomes 𝑓: 0.0000053 (0 hom. 2 hem.)
• Consequence: ARHGAP4 NM_001666.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.59
• 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

ENSG00000284987 (HGNC:):

ACMG classification

Our verdict: Likely_benign. The variant received -5 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.29792327).
• 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.2666G>T	p.Arg889Leu	missense	Exon 22 of 22	NP_001657.3
	ARHGAP4	NM_001164741.2		c.2786G>T	p.Arg929Leu	missense	Exon 23 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.2666G>T	p.Arg889Leu	missense	Exon 22 of 22	ENSP00000203786.8	P98171-1
	ARHGAP4	ENST00000370028.7	TSL:1	c.2786G>T	p.Arg929Leu	missense	Exon 23 of 23	ENSP00000359045.3	P98171-2
	ENSG00000284987	ENST00000646191.1		n.96+1166G>T		intron	N/A	ENSP00000493873.1	A0A2R8Y4P6

Frequencies

GnomAD3 genomes Cov.: 25

GnomAD4 exome AF: 0.00000527 AC: 5 AN: 948025 Hom.: 0 Cov.: 30 AF XY: 0.00000677 AC XY: 2 AN XY: 295505

African (AFR) AF: 0.00 AC: 0 AN: 20351

American (AMR) AF: 0.00 AC: 0 AN: 17622

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 13032

East Asian (EAS) AF: 0.00 AC: 0 AN: 24004

South Asian (SAS) AF: 0.00 AC: 0 AN: 31491

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 35245

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3514

European-Non Finnish (NFE) AF: 0.00000654 AC: 5 AN: 763972

Other (OTH) AF: 0.00 AC: 0 AN: 38794

GnomAD4 genome Cov.: 25

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Benign	-0.34	T
BayesDel_noAF	Benign	-0.73
CADD	Benign	21
DANN	Uncertain	0.99
DEOGEN2	Benign	0.11	T
FATHMM_MKL	Benign	0.41	N
LIST_S2	Uncertain	0.89	D
M_CAP	Benign	0.032	D
MetaRNN	Benign	0.30	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.1	L
PhyloP100		3.6
PrimateAI	Uncertain	0.49	T
PROVEAN	Benign	-2.1	N
REVEL	Benign	0.040
Sift	Benign	0.092	T
Sift4G	Uncertain	0.043	D
Polyphen		0.15	B
Vest4		0.47
MutPred		0.24		Loss of MoRF binding (P = 0.0054)
MVP		0.18
MPC		0.053
ClinPred		0.59	D
GERP RS		4.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Varity_R		0.16
gMVP		0.43
Mutation Taster		=99/1	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: rs149873165; hg19: chrX-153173358;