Genetic Variant NM_001025616.3:c.-20-80delT (chr4-85570431-CT-C) – ACMG Classification: Likely_benign (-4 pts)

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BS2

The NM_001025616.3(ARHGAP24):c.-20-80delT variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00792 in 419,810 control chromosomes in the GnomAD database, including 2 homozygotes. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.00020 ( 0 hom., cov: 0)

Exomes 𝑓: 0.011 ( 2 hom. )

Consequence

ARHGAP24
NM_001025616.3 intron

Scores

Not classified

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 1.25

Publications

1 publications found

Variant links:

Genes affected

ARHGAP24 (HGNC:25361): (Rho GTPase activating protein 24) This gene encodes a Rho-GTPase activating protein, which is specific for the small GTPase family member Rac. Binding of the encoded protein by filamin A targets it to sites of membrane protrusion, where it antognizes Rac. This results in suppression of lamellae formation and promotion of retraction to regulate cell polarity. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Sep 2016]

ARHGAP24 Gene-Disease associations (from GenCC):

familial idiopathic steroid-resistant nephrotic syndrome
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ARHGAP24 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -4 ACMG points.

BS2

High AC in GnomAd4 at 26 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ARHGAP24	NM_001025616.3 link	c.-20-80delT		intron_variant	Intron 1 of 9	ENST00000395184.6	NP_001020787.2	Q8N264-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ARHGAP24	ENST00000395184.6 link	c.-20-80delT		intron_variant	Intron 1 of 9	2	NM_001025616.3	ENSP00000378611.1		Q8N264-1

Frequencies

GnomAD3 genomes

AF:

0.000199

AC:

AN:

130788

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000830

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000163

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000915

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000259

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.0114

AC:

3300

AN:

288968

Hom.:

AF XY:

0.0114

AC XY:

1717

AN XY:

150944

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00595

AC:

AN:

7226

American (AMR)

AF:

0.0102

AC:

102

AN:

9964

Ashkenazi Jewish (ASJ)

AF:

0.0121

AC:

109

AN:

9006

East Asian (EAS)

AF:

0.00227

AC:

AN:

20302

South Asian (SAS)

AF:

0.00950

AC:

166

AN:

17468

European-Finnish (FIN)

AF:

0.0130

AC:

265

AN:

20308

Middle Eastern (MID)

AF:

0.00495

AC:

AN:

2624

European-Non Finnish (NFE)

AF:

0.0127

AC:

2365

AN:

186624

Other (OTH)

AF:

0.0124

AC:

191

AN:

15446

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.299

Heterozygous variant carriers

343

686

1028

1371

1714

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.000199

AC:

AN:

130842

Hom.:

Cov.:

AF XY:

0.000130

AC XY:

AN XY:

61568

show subpopulations

African (AFR)

AF:

0.0000828

AC:

AN:

36232

American (AMR)

AF:

0.000163

AC:

AN:

12300

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3206

East Asian (EAS)

AF:

0.00

AC:

AN:

4848

South Asian (SAS)

AF:

0.00

AC:

AN:

4152

European-Finnish (FIN)

AF:

0.000915

AC:

AN:

5466

Middle Eastern (MID)

AF:

0.00

AC:

AN:

204

European-Non Finnish (NFE)

AF:

0.000259

AC:

AN:

61810

Other (OTH)

AF:

0.00

AC:

AN:

1752

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.419

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

PhyloP100

1.3

Mutation Taster

=100/0

polymorphism

(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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NM_001025616.3:c.-20-80delT

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over