17-81868810-TG-TGG

Variant names:

• chr17-81868810-T-TG
• rs757131763
• NM_004309.6:c.*65dupC

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 4P and 5B. PVS1_Strong BS1_Supporting BS2

The NM_001301242.2(ARHGDIA):​c.568dupC​(p.Gln190ProfsTer11) 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
• Publications: 0 publications found

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 Gene-Disease associations (from GenCC):

• nephrotic syndrome, type 8

  Inheritance: AR Classification: STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, ClinGen
• familial idiopathic steroid-resistant nephrotic syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Likely_benign. The variant received -1 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. Fraction of 0.44 CDS is truncated, and there are 1 pathogenic variants in the truncated region.
• BS1: Variant frequency is greater than expected in population eas. GnomAdExome4 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 GnomAdExome4. There are 570 alleles in the male GnomAdExome4 subpopulation. Median coverage is 35. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High Homozygotes in GnomAdExome4 at 3 AR,AD gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001301242.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ARHGDIA	NM_004309.6	MANE Select	c.*65dupC		3_prime_UTR	Exon 6 of 6	NP_004300.1	P52565-1
	ARHGDIA	NM_001301242.2		c.568dupC	p.Gln190ProfsTer11	frameshift	Exon 7 of 7	NP_001288171.1
	ARHGDIA	NM_001301243.2		c.*65dupC		3_prime_UTR	Exon 5 of 5	NP_001288172.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ARHGDIA	ENST00000269321.12	TSL:1 MANE Select	c.*65dupC		3_prime_UTR	Exon 6 of 6	ENSP00000269321.7	P52565-1
	ARHGDIA	ENST00000580685.5	TSL:1	c.*65dupC		3_prime_UTR	Exon 5 of 5	ENSP00000464205.1	P52565-1
	ARHGDIA	ENST00000583868.5	TSL:3	c.568dupC	p.Gln190ProfsTer11	frameshift	Exon 7 of 7	ENSP00000462209.1	J3KRY1

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

GnomAD2 exomes AF: 0.000696 AC: 142 AN: 204026 AF XY: 0.000659

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 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

African (AFR) AF: 0.000782 AC: 9 AN: 11504

American (AMR) AF: 0.0000344 AC: 1 AN: 29104

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 10586

East Asian (EAS) AF: 0.0189 AC: 220 AN: 11656

South Asian (SAS) AF: 0.00165 AC: 82 AN: 49560

European-Finnish (FIN) AF: 0.000280 AC: 7 AN: 24968

Middle Eastern (MID) AF: 0.000370 AC: 1 AN: 2704

European-Non Finnish (NFE) AF: 0.00334 AC: 803 AN: 240252

Other (OTH) AF: 0.00163 AC: 27 AN: 16558

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

African (AFR) AF: 0.000284 AC: 3 AN: 10558

American (AMR) AF: 0.000525 AC: 2 AN: 3810

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 990

East Asian (EAS) AF: 0.00794 AC: 16 AN: 2016

South Asian (SAS) AF: 0.00296 AC: 4 AN: 1352

European-Finnish (FIN) AF: 0.000480 AC: 1 AN: 2082

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 150

European-Non Finnish (NFE) AF: 0.00250 AC: 48 AN: 19204

Other (OTH) AF: 0.00 AC: 0 AN: 550

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Finnish congenital nephrotic syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.064
Mutation Taster		=100/0	disease causing (ClinVar)

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: rs757131763; hg19: chr17-79826686; COSMIC: COSV99482611; COSMIC: COSV99482611;