rs139401482

Variant names:

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

Your query was ambiguous. Multiple possible variants found:

• chrX-153907968-G-A
• chrX-153907968-G-C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001666.5(ARHGAP4):​c.2608-6C>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 0.0407 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. 3/3 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, intron
• Scores: Splicing: ADA: 0.00007859
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.182
• Publications: 1 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: Benign. The variant received -20 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_multiple_submitters_no_conflicts, 2 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 the male GnomAd4 subpopulation. Median coverage is 24. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 49 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ARHGAP4	NM_001666.5	c.2608-6C>T		splice_region_variant, intron_variant	Intron 21 of 21	ENST00000350060.10	NP_001657.3
ARHGAP4	NM_001164741.2	c.2728-6C>T		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>T		splice_region_variant, intron_variant	Intron 21 of 21	1	NM_001666.5	ENSP00000203786.8
ENSG00000284987	ENST00000646191.1	n.96+1102C>T		intron_variant	Intron 1 of 4			ENSP00000493873.1

Frequencies

GnomAD3 genomes AF: 0.0298 AC: 3336 AN: 111878 Hom.: 49 Cov.: 24

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

GnomAD2 exomes AF: 0.0299 AC: 3611 AN: 120835 AF XY: 0.0303

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 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

African (AFR) AF: 0.00427 AC: 96 AN: 22468

American (AMR) AF: 0.0101 AC: 262 AN: 25973

Ashkenazi Jewish (ASJ) AF: 0.0439 AC: 714 AN: 16260

East Asian (EAS) AF: 0.0000394 AC: 1 AN: 25354

South Asian (SAS) AF: 0.00496 AC: 215 AN: 43316

European-Finnish (FIN) AF: 0.0642 AC: 2455 AN: 38234

Middle Eastern (MID) AF: 0.00782 AC: 30 AN: 3837

European-Non Finnish (NFE) AF: 0.0466 AC: 37541 AN: 805412

Other (OTH) AF: 0.0365 AC: 1545 AN: 42383

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

African (AFR) AF: 0.00616 AC: 190 AN: 30859

American (AMR) AF: 0.0157 AC: 168 AN: 10675

Ashkenazi Jewish (ASJ) AF: 0.0450 AC: 119 AN: 2645

East Asian (EAS) AF: 0.00 AC: 0 AN: 3530

South Asian (SAS) AF: 0.00671 AC: 18 AN: 2683

European-Finnish (FIN) AF: 0.0628 AC: 385 AN: 6133

Middle Eastern (MID) AF: 0.0230 AC: 5 AN: 217

European-Non Finnish (NFE) AF: 0.0455 AC: 2409 AN: 52971

Other (OTH) AF: 0.0221 AC: 34 AN: 1536

Alfa AF: 0.0401 Hom.: 339

Bravo AF: 0.0255

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Mar 28, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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 -

not provided Benign:1

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	0.56
DANN	Benign	0.50
PhyloP100		0.18
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs139401482; hg19: chrX-153173422; COSMIC: COSV109432311; COSMIC: COSV109432311;