X-153909539-C-T

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP4_Strong BP6_Moderate BS2

The NM_001666.5(ARHGAP4):c.2415-4G>A variant causes a splice region, splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0116 in 1,199,563 control chromosomes in the GnomAD database, including 81 homozygotes. There are 4,398 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. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.0089 (2 hom., 263 hem., cov: 26)
  • Exomes 𝑓: 0.012 (79 hom. 4135 hem.)
• Consequence: ARHGAP4 NM_001666.5 splice_region, splice_polypyrimidine_tract, intron
• Scores: Splicing: ADA: 0.00002170
• Clinical Significance: Benign criteria provided, single submitter B:1
• 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 Benign. Variant got -10 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.81).
• BP6: Variant X-153909539-C-T is Benign according to our data. Variant chrX-153909539-C-T is described in ClinVar as [Benign]. Clinvar id is 771947.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chrX-153909539-C-T is described in Lovd as [Likely_benign].
• BS2: High Homozygotes in GnomAd at 2 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ARHGAP4	NM_001666.5	c.2415-4G>A		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		ENST00000350060.10
ARHGAP4	NM_001164741.2	c.2535-4G>A		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ARHGAP4	ENST00000350060.10	c.2415-4G>A		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		1	NM_001666.5	P2

Frequencies

GnomAD3 genomes AF: 0.00888 AC: 992 AN: 111676 Hom.: 2 Cov.: 26 AF XY: 0.00780 AC XY: 264 AN XY: 33842

Gnomad AFR AF: 0.00176

Gnomad AMI AF: 0.00293

Gnomad AMR AF: 0.00537

Gnomad ASJ AF: 0.00605

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00879

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0150

Gnomad OTH AF: 0.0113

GnomAD3 exomes AF: 0.00802 AC: 1326 AN: 165238 Hom.: 12 AF XY: 0.00680 AC XY: 365 AN XY: 53714

Gnomad AFR exome AF: 0.00138

Gnomad AMR exome AF: 0.00520

Gnomad ASJ exome AF: 0.00446

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000619

Gnomad FIN exome AF: 0.0122

Gnomad NFE exome AF: 0.0128

Gnomad OTH exome AF: 0.00909

GnomAD4 exome AF: 0.0119 AC: 12976 AN: 1087832 Hom.: 79 Cov.: 33 AF XY: 0.0116 AC XY: 4135 AN XY: 354962

Gnomad4 AFR exome AF: 0.00183

Gnomad4 AMR exome AF: 0.00551

Gnomad4 ASJ exome AF: 0.00584

Gnomad4 EAS exome AF: 0.0000664

Gnomad4 SAS exome AF: 0.000134

Gnomad4 FIN exome AF: 0.0123

Gnomad4 NFE exome AF: 0.0139

Gnomad4 OTH exome AF: 0.0102

GnomAD4 genome AF: 0.00888 AC: 992 AN: 111731 Hom.: 2 Cov.: 26 AF XY: 0.00776 AC XY: 263 AN XY: 33907

Gnomad4 AFR AF: 0.00175

Gnomad4 AMR AF: 0.00537

Gnomad4 ASJ AF: 0.00605

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00879

Gnomad4 NFE AF: 0.0150

Gnomad4 OTH AF: 0.0111

Alfa AF: 0.00721 Hom.: 54

Bravo AF: 0.00770

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Dec 31, 2019

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
Cadd	Benign	0.74
Dann	Benign	0.80

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000022
dbscSNV1_RF	Benign	0.0020
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

Publications

LitVar

Other links and lift over

dbSNP: rs41299128; hg19: chrX-153174993;