NM_001666.5:c.2409C>G

Variant names:

• chrX-153909746-G-C
• rs374821227
• NM_001666.5:c.2409C>G

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 2P and 3B. PM2 BP4_Moderate BP7

The NM_001666.5(ARHGAP4):​c.2409C>G​(p.Pro803Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000186 in 1,075,411 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. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. P803P) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 24)
  • Exomes 𝑓: 0.0000019 (0 hom. 1 hem.)
• Consequence: ARHGAP4 NM_001666.5 synonymous
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -3.04
• 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 -1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (REVEL=0.03).
• BP7: Synonymous conserved (PhyloP=-3.04 with no splicing effect.

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.2409C>G	p.Pro803Pro	synonymous	Exon 19 of 22	NP_001657.3
	ARHGAP4	NM_001164741.2		c.2529C>G	p.Pro843Pro	synonymous	Exon 20 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.2409C>G	p.Pro803Pro	synonymous	Exon 19 of 22	ENSP00000203786.8	P98171-1
	ARHGAP4	ENST00000370028.7	TSL:1	c.2529C>G	p.Pro843Pro	synonymous	Exon 20 of 23	ENSP00000359045.3	P98171-2
	ARHGAP4	ENST00000968871.1		c.2427C>G	p.Pro809Pro	synonymous	Exon 19 of 22	ENSP00000638930.1

Frequencies

GnomAD3 genomes Cov.: 24

GnomAD4 exome AF: 0.00000186 AC: 2 AN: 1075411 Hom.: 0 Cov.: 35 AF XY: 0.00000288 AC XY: 1 AN XY: 347587

African (AFR) AF: 0.00 AC: 0 AN: 26085

American (AMR) AF: 0.00 AC: 0 AN: 32840

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 18103

East Asian (EAS) AF: 0.00 AC: 0 AN: 29814

South Asian (SAS) AF: 0.0000198 AC: 1 AN: 50497

European-Finnish (FIN) AF: 0.0000264 AC: 1 AN: 37825

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3537

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 831579

Other (OTH) AF: 0.00 AC: 0 AN: 45131

GnomAD4 genome Cov.: 24

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	0.034
DANN	Benign	0.40
PhyloP100		-3.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0

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: rs374821227; hg19: chrX-153175200;