rs71599418

Variant names:

• chr4-85570437-T-C
• rs71599418
• NM_001025616.3:c.-20-85T>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_001025616.3(ARHGAP24):​c.-20-85T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.024 in 772,098 control chromosomes in the GnomAD database, including 494 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.021 (58 hom., cov: 29)
  • Exomes 𝑓: 0.025 (436 hom.)
• Consequence: ARHGAP24 NM_001025616.3 intron
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 1.77
• Publications: 1 publications found

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

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BP6: Variant 4-85570437-T-C is Benign according to our data. Variant chr4-85570437-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 1189401.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 = 0.0215 (3115/144996) while in subpopulation NFE AF = 0.0335 (2248/67076). AF 95% confidence interval is 0.0324. There are 58 homozygotes in GnomAd4. There are 1397 alleles in the male GnomAd4 subpopulation. Median coverage is 29. This position passed quality control check.
• BS2: High AC in GnomAd4 at 3115 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ARHGAP24	NM_001025616.3	c.-20-85T>C		intron_variant	Intron 1 of 9	ENST00000395184.6	NP_001020787.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ARHGAP24	ENST00000395184.6	c.-20-85T>C		intron_variant	Intron 1 of 9	2	NM_001025616.3	ENSP00000378611.1

Frequencies

GnomAD3 genomes AF: 0.0215 AC: 3116 AN: 144912 Hom.: 58 Cov.: 29

Gnomad AFR AF: 0.00581

Gnomad AMI AF: 0.0463

Gnomad AMR AF: 0.0166

Gnomad ASJ AF: 0.00866

Gnomad EAS AF: 0.000412

Gnomad SAS AF: 0.00820

Gnomad FIN AF: 0.0300

Gnomad MID AF: 0.00680

Gnomad NFE AF: 0.0335

Gnomad OTH AF: 0.0154

GnomAD4 exome AF: 0.0246 AC: 15411 AN: 627102 Hom.: 436 AF XY: 0.0242 AC XY: 7912 AN XY: 327084

African (AFR) AF: 0.00394 AC: 57 AN: 14474

American (AMR) AF: 0.00864 AC: 182 AN: 21076

Ashkenazi Jewish (ASJ) AF: 0.00831 AC: 142 AN: 17078

East Asian (EAS) AF: 0.000347 AC: 9 AN: 25930

South Asian (SAS) AF: 0.00953 AC: 455 AN: 47738

European-Finnish (FIN) AF: 0.0331 AC: 1146 AN: 34606

Middle Eastern (MID) AF: 0.00233 AC: 9 AN: 3870

European-Non Finnish (NFE) AF: 0.0297 AC: 12819 AN: 431924

Other (OTH) AF: 0.0195 AC: 592 AN: 30406

GnomAD4 genome AF: 0.0215 AC: 3115 AN: 144996 Hom.: 58 Cov.: 29 AF XY: 0.0200 AC XY: 1397 AN XY: 69986

African (AFR) AF: 0.00579 AC: 226 AN: 39020

American (AMR) AF: 0.0165 AC: 228 AN: 13834

Ashkenazi Jewish (ASJ) AF: 0.00866 AC: 30 AN: 3464

East Asian (EAS) AF: 0.000413 AC: 2 AN: 4844

South Asian (SAS) AF: 0.00822 AC: 38 AN: 4622

European-Finnish (FIN) AF: 0.0300 AC: 268 AN: 8928

Middle Eastern (MID) AF: 0.00735 AC: 2 AN: 272

European-Non Finnish (NFE) AF: 0.0335 AC: 2248 AN: 67076

Other (OTH) AF: 0.0153 AC: 31 AN: 2028

Alfa AF: 0.0274 Hom.: 18

Bravo AF: 0.0196

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Jun 07, 2020

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	4.9
DANN	Benign	0.51
PhyloP100		1.8
Mutation Taster		=100/0	polymorphism

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: rs71599418; hg19: chr4-86491590;