rs139401482

chrX-153907968-G-A

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_001666.5(ARHGAP4):c.2608-6C>T 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 0.0407 in 1,135,169 control chromosomes in the GnomAD database, including 771 homozygotes. There are 14,164 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 2/2 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.030 (49 hom., 975 hem., cov: 24)
  • Exomes 𝑓: 0.042 (722 hom. 13189 hem.)
• Consequence: ARHGAP4 NM_001666.5 splice_region, splice_polypyrimidine_tract, intron
• Scores: Splicing: ADA: 0.00007859
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.182

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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.89).
• BP6: Variant X-153907968-G-A is Benign according to our data. Variant chrX-153907968-G-A is described in ClinVar as [Benign]. Clinvar id is 402404.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0298 (3334/111932) while in subpopulation NFE AF= 0.0455 (2409/52971). AF 95% confidence interval is 0.044. There are 49 homozygotes in gnomad4. There are 975 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 49 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ARHGAP4	NM_001666.5	c.2608-6C>T		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		ENST00000350060.10
ARHGAP4	NM_001164741.2	c.2728-6C>T		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.2608-6C>T		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		1	NM_001666.5	P2

Frequencies

GnomAD3 genomes AF: 0.0298 AC: 3336 AN: 111878 Hom.: 49 Cov.: 24 AF XY: 0.0286 AC XY: 976 AN XY: 34078

Gnomad AFR AF: 0.00617

Gnomad AMI AF: 0.00878

Gnomad AMR AF: 0.0158

Gnomad ASJ AF: 0.0450

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00669

Gnomad FIN AF: 0.0628

Gnomad MID AF: 0.0210

Gnomad NFE AF: 0.0455

Gnomad OTH AF: 0.0224

GnomAD3 exomes AF: 0.0299 AC: 3611 AN: 120835 Hom.: 55 AF XY: 0.0303 AC XY: 1075 AN XY: 35447

Gnomad AFR exome AF: 0.00595

Gnomad AMR exome AF: 0.00916

Gnomad ASJ exome AF: 0.0438

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00322

Gnomad FIN exome AF: 0.0646

Gnomad NFE exome AF: 0.0395

Gnomad OTH exome AF: 0.0290

GnomAD4 exome AF: 0.0419 AC: 42859 AN: 1023237 Hom.: 722 Cov.: 29 AF XY: 0.0406 AC XY: 13189 AN XY: 324755

Gnomad4 AFR exome AF: 0.00427

Gnomad4 AMR exome AF: 0.0101

Gnomad4 ASJ exome AF: 0.0439

Gnomad4 EAS exome AF: 0.0000394

Gnomad4 SAS exome AF: 0.00496

Gnomad4 FIN exome AF: 0.0642

Gnomad4 NFE exome AF: 0.0466

Gnomad4 OTH exome AF: 0.0365

GnomAD4 genome AF: 0.0298 AC: 3334 AN: 111932 Hom.: 49 Cov.: 24 AF XY: 0.0286 AC XY: 975 AN XY: 34142

Gnomad4 AFR AF: 0.00616

Gnomad4 AMR AF: 0.0157

Gnomad4 ASJ AF: 0.0450

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00671

Gnomad4 FIN AF: 0.0628

Gnomad4 NFE AF: 0.0455

Gnomad4 OTH AF: 0.0221

Alfa AF: 0.0401 Hom.: 339

Bravo AF: 0.0255

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Mar 28, 2016

Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Frequency -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
Cadd	Benign	0.56
Dann	Benign	0.50
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000079
dbscSNV1_RF	Benign	0.0060
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: rs139401482; hg19: chrX-153173422;