X-153907968-G-C

Variant names:

• chrX-153907968-G-C
• rs139401482
• NM_001666.5:c.2608-6C>G

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The NM_001666.5(ARHGAP4):​c.2608-6C>G variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000586 in 1,023,382 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. 3/3 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 24)
  • Exomes 𝑓: 0.0000059 (0 hom. 1 hem.)
• Consequence: ARHGAP4 NM_001666.5 splice_region, intron
• Scores: Splicing: ADA: 0.0003705
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.182
• 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 -4 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.86).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ARHGAP4	NM_001666.5	c.2608-6C>G		splice_region_variant, intron_variant	Intron 21 of 21	ENST00000350060.10	NP_001657.3
ARHGAP4	NM_001164741.2	c.2728-6C>G		splice_region_variant, intron_variant	Intron 22 of 22		NP_001158213.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ARHGAP4	ENST00000350060.10	c.2608-6C>G		splice_region_variant, intron_variant	Intron 21 of 21	1	NM_001666.5	ENSP00000203786.8
ENSG00000284987	ENST00000646191.1	n.96+1102C>G		intron_variant	Intron 1 of 4			ENSP00000493873.1

Frequencies

GnomAD3 genomes Cov.: 24

GnomAD4 exome AF: 0.00000586 AC: 6 AN: 1023382 Hom.: 0 Cov.: 29 AF XY: 0.00000308 AC XY: 1 AN XY: 324784

African (AFR) AF: 0.00 AC: 0 AN: 22468

American (AMR) AF: 0.00 AC: 0 AN: 25975

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 16265

East Asian (EAS) AF: 0.00 AC: 0 AN: 25354

South Asian (SAS) AF: 0.000139 AC: 6 AN: 43318

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 38248

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3837

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 805528

Other (OTH) AF: 0.00 AC: 0 AN: 42389

GnomAD4 genome Cov.: 24

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	0.63
DANN	Benign	0.54
PhyloP100		0.18
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00037
dbscSNV1_RF	Benign	0.036
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: rs139401482; hg19: chrX-153173422;