17-81868810-TG-TGG

Position:

• chr17-81868810-TG-TGG

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BS1_Supporting BS2

The NM_001301242.2(ARHGDIA):​c.568dupC​(p.Gln190fs) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0028 in 437,842 control chromosomes in the GnomAD database, including 3 homozygotes. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.0018 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0029 (3 hom.)
• Consequence: ARHGDIA NM_001301242.2 frameshift
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.0640

Genes affected

ARHGDIA (HGNC:678): (Rho GDP dissociation inhibitor alpha) This gene encodes a protein that plays a key role in the regulation of signaling through Rho GTPases. The encoded protein inhibits the disassociation of Rho family members from GDP (guanine diphosphate), thereby maintaining these factors in an inactive state. Activity of this protein is important in a variety of cellular processes, and expression of this gene may be altered in tumors. Mutations in this gene have been found in individuals with nephrotic syndrome, type 8. Alternate splicing results in multiple transcript variants. [provided by RefSeq, Jul 2014]

ARHGDIA (HGNC:):

ACMG classification

Verdict is Likely_benign. Variant got -5 ACMG points.

• BS1: Variant frequency is greater than expected in population eas. gnomad4_exome allele frequency = 0.0029 (1150/396892) while in subpopulation EAS AF= 0.0189 (220/11656). AF 95% confidence interval is 0.0168. There are 3 homozygotes in gnomad4_exome. There are 570 alleles in male gnomad4_exome subpopulation. Median coverage is 35. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High Homozygotes in GnomAdExome4 at 3 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ARHGDIA	NM_004309.6	c.*65dupC		3_prime_UTR_variant	6/6	ENST00000269321.12	NP_004300.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ARHGDIA	ENST00000269321	c.*65dupC		3_prime_UTR_variant	6/6	1	NM_004309.6	ENSP00000269321.7

Frequencies

GnomAD3 genomes AF: 0.00181 AC: 74 AN: 40890 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000285

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000527

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00793

Gnomad SAS AF: 0.00296

Gnomad FIN AF: 0.000480

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00250

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000696 AC: 142 AN: 204026 Hom.: 0 AF XY: 0.000659 AC XY: 74 AN XY: 112298

Gnomad AFR exome AF: 0.000229

Gnomad AMR exome AF: 0.0000387

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00170

Gnomad SAS exome AF: 0.00106

Gnomad FIN exome AF: 0.000159

Gnomad NFE exome AF: 0.000894

Gnomad OTH exome AF: 0.000208

GnomAD4 exome AF: 0.00290 AC: 1150 AN: 396892 Hom.: 3 Cov.: 35 AF XY: 0.00263 AC XY: 570 AN XY: 216800

Gnomad4 AFR exome AF: 0.000782

Gnomad4 AMR exome AF: 0.0000344

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0189

Gnomad4 SAS exome AF: 0.00165

Gnomad4 FIN exome AF: 0.000280

Gnomad4 NFE exome AF: 0.00334

Gnomad4 OTH exome AF: 0.00163

GnomAD4 genome AF: 0.00181 AC: 74 AN: 40950 Hom.: 0 Cov.: 32 AF XY: 0.00193 AC XY: 39 AN XY: 20244

Gnomad4 AFR AF: 0.000284

Gnomad4 AMR AF: 0.000525

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00794

Gnomad4 SAS AF: 0.00296

Gnomad4 FIN AF: 0.000480

Gnomad4 NFE AF: 0.00250

Gnomad4 OTH AF: 0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Finnish congenital nephrotic syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Genomic Research Center, Shahid Beheshti University of Medical Sciences

Dec 18, 2017

- -

Computational scores

Source: dbNSFP v4.3

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

LitVar

Other links and lift over

dbSNP: rs757131763; hg19: chr17-79826686;