X-153910800-A-G

Variant names:

• chrX-153910800-A-G
• rs2070097
• NM_001666.5:c.1716T>C

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BA1

The NM_001666.5(ARHGAP4):​c.1716T>C​(p.His572His) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.446 in 1,186,770 control chromosomes in the GnomAD database, including 87,749 homozygotes. There are 171,478 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.56 (14021 hom., 17712 hem., cov: 22)
  • Exomes 𝑓: 0.44 (73728 hom. 153766 hem.)
• Consequence: ARHGAP4 NM_001666.5 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -1.14
• Publications: 16 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

ENSG00000302519 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -19 ACMG points.

• BP4: Computational evidence support a benign effect (REVEL=0.036).
• BP6: Variant X-153910800-A-G is Benign according to our data. Variant chrX-153910800-A-G is described in ClinVar as Benign. ClinVar VariationId is 402391.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-1.14 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.85 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ARHGAP4	NM_001666.5	c.1716T>C	p.His572His	synonymous_variant	Exon 15 of 22	ENST00000350060.10	NP_001657.3
ARHGAP4	NM_001164741.2	c.1836T>C	p.His612His	synonymous_variant	Exon 16 of 23		NP_001158213.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ARHGAP4	ENST00000350060.10	c.1716T>C	p.His572His	synonymous_variant	Exon 15 of 22	1	NM_001666.5	ENSP00000203786.8

Frequencies

GnomAD3 genomes AF: 0.557 AC: 61229 AN: 109981 Hom.: 14015 Cov.: 22

Gnomad AFR AF: 0.858

Gnomad AMI AF: 0.217

Gnomad AMR AF: 0.604

Gnomad ASJ AF: 0.455

Gnomad EAS AF: 0.702

Gnomad SAS AF: 0.733

Gnomad FIN AF: 0.364

Gnomad MID AF: 0.513

Gnomad NFE AF: 0.387

Gnomad OTH AF: 0.574

GnomAD2 exomes AF: 0.532 AC: 78582 AN: 147643 AF XY: 0.512

Gnomad AFR exome AF: 0.869

Gnomad AMR exome AF: 0.693

Gnomad ASJ exome AF: 0.457

Gnomad EAS exome AF: 0.714

Gnomad FIN exome AF: 0.376

Gnomad NFE exome AF: 0.375

Gnomad OTH exome AF: 0.486

GnomAD4 exome AF: 0.435 AC: 468443 AN: 1076741 Hom.: 73728 Cov.: 52 AF XY: 0.442 AC XY: 153766 AN XY: 348057

African (AFR) AF: 0.875 AC: 22789 AN: 26030

American (AMR) AF: 0.683 AC: 23123 AN: 33847

Ashkenazi Jewish (ASJ) AF: 0.469 AC: 8613 AN: 18360

East Asian (EAS) AF: 0.727 AC: 21499 AN: 29582

South Asian (SAS) AF: 0.731 AC: 37107 AN: 50734

European-Finnish (FIN) AF: 0.372 AC: 14348 AN: 38561

Middle Eastern (MID) AF: 0.565 AC: 2256 AN: 3994

European-Non Finnish (NFE) AF: 0.381 AC: 316823 AN: 830493

Other (OTH) AF: 0.485 AC: 21885 AN: 45140

GnomAD4 genome AF: 0.557 AC: 61285 AN: 110029 Hom.: 14021 Cov.: 22 AF XY: 0.548 AC XY: 17712 AN XY: 32319

African (AFR) AF: 0.858 AC: 25881 AN: 30151

American (AMR) AF: 0.604 AC: 6359 AN: 10524

Ashkenazi Jewish (ASJ) AF: 0.455 AC: 1194 AN: 2622

East Asian (EAS) AF: 0.701 AC: 2409 AN: 3435

South Asian (SAS) AF: 0.732 AC: 1859 AN: 2540

European-Finnish (FIN) AF: 0.364 AC: 2155 AN: 5927

Middle Eastern (MID) AF: 0.507 AC: 109 AN: 215

European-Non Finnish (NFE) AF: 0.387 AC: 20299 AN: 52446

Other (OTH) AF: 0.581 AC: 877 AN: 1509

Alfa AF: 0.459 Hom.: 33746

Bravo AF: 0.590

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: MAF -

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	-0.87
CADD	Benign	0.014
DANN	Benign	0.41
PhyloP100		-1.1
PromoterAI		-0.015	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
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: rs2070097; hg19: chrX-153176254; COSMIC: COSV61685749; COSMIC: COSV61685749;