NM_001666.5:c.1716T>C

Variant names:

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_ModerateBP6_Very_StrongBP7BA1

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

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: -1.14

Publications

16 publications found

Variant links:

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

ARHGAP4 links:

ENSG00000302519 (HGNC:):

ENSG00000302519 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001666.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ARHGAP4	NM_001666.5	MANE Select	c.1716T>C	p.His572His	synonymous	Exon 15 of 22	NP_001657.3
	ARHGAP4	NM_001164741.2		c.1836T>C	p.His612His	synonymous	Exon 16 of 23	NP_001158213.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
ARHGAP4	ENST00000350060.10	TSL:1 MANE Select	c.1716T>C	p.His572His	synonymous	Exon 15 of 22	ENSP00000203786.8
ARHGAP4	ENST00000370028.7	TSL:1	c.1836T>C	p.His612His	synonymous	Exon 16 of 23	ENSP00000359045.3
ARHGAP4	ENST00000370016.5	TSL:5	c.1653T>C	p.His551His	synonymous	Exon 14 of 21	ENSP00000359033.1

Frequencies

GnomAD3 genomes

AF:

0.557

AC:

61229

AN:

109981

Hom.:

14015

Cov.:

show subpopulations

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

show subpopulations

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.:

AF XY:

0.442

AC XY:

153766

AN XY:

348057

show subpopulations

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

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.486

Heterozygous variant carriers

11362

22724

34086

45448

56810

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

11432

22864

34296

45728

57160

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.557

AC:

61285

AN:

110029

Hom.:

14021

Cov.:

AF XY:

0.548

AC XY:

17712

AN XY:

32319

show subpopulations

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

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

810

1620

2431

3241

4051

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

540

1080

1620

2160

2700

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.459

Hom.:

33746

Bravo

AF:

0.590

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

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 v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.87

CADD

Benign

0.014

(source)

DANN

Benign

0.41

PhyloP100

-1.1

PromoterAI

-0.015

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over