NM_001666.5:c.2415-4G>T

Variant names:

• chrX-153909539-C-A
• rs41299128
• NM_001666.5:c.2415-4G>T

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_001666.5(ARHGAP4):​c.2415-4G>T variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000333 in 1,199,544 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: 𝑓 0.0000090 (0 hom., 0 hem., cov: 26)
  • Exomes 𝑓: 0.0000028 (0 hom. 1 hem.)
• Consequence: ARHGAP4 NM_001666.5 splice_region, intron
• Scores: Splicing: ADA: 0.00003744
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.142

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]

ACMG classification

Verdict is Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.81).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ARHGAP4	NM_001666.5	c.2415-4G>T		splice_region_variant, intron_variant	Intron 19 of 21	ENST00000350060.10	NP_001657.3
ARHGAP4	NM_001164741.2	c.2535-4G>T		splice_region_variant, intron_variant	Intron 20 of 22		NP_001158213.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ARHGAP4	ENST00000350060.10	c.2415-4G>T		splice_region_variant, intron_variant	Intron 19 of 21	1	NM_001666.5	ENSP00000203786.8

Frequencies

GnomAD3 genomes AF: 0.00000895 AC: 1 AN: 111676 Hom.: 0 Cov.: 26 AF XY: 0.00 AC XY: 0 AN XY: 33842

Gnomad AFR AF: 0.0000326

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

GnomAD4 exome AF: 0.00000276 AC: 3 AN: 1087868 Hom.: 0 Cov.: 33 AF XY: 0.00000282 AC XY: 1 AN XY: 354970

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000358

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.00000895 AC: 1 AN: 111676 Hom.: 0 Cov.: 26 AF XY: 0.00 AC XY: 0 AN XY: 33842

Gnomad4 AFR AF: 0.0000326

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Bravo AF: 0.0000151

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	1.1
DANN	Benign	0.67

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000037
dbscSNV1_RF	Benign	0.0040
SpliceAI score (max)		0.050		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs41299128; hg19: chrX-153174993;