17-81868810-TG-TGGGGGG

Variant names:

• chr17-81868810-T-TGGGGG
• rs757131763
• NM_004309.6:c.*61_*65dupCCCCC

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PVS1_Strong PM2

The NM_001301242.2(ARHGDIA):​c.564_568dupCCCCC​(p.Gln190ProfsTer146) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 32)
• Consequence: ARHGDIA NM_001301242.2 frameshift
• Clinical Significance: Not reported in ClinVar
• 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_pathogenic. The variant received 6 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.
• PM2: Very rare variant in population databases, with high coverage

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.*61_*65dupCCCCC		3_prime_UTR	Exon 6 of 6	NP_004300.1	P52565-1
	ARHGDIA	NM_001301242.2		c.564_568dupCCCCC	p.Gln190ProfsTer146	frameshift	Exon 7 of 7	NP_001288171.1
	ARHGDIA	NM_001301243.2		c.*61_*65dupCCCCC		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.*61_*65dupCCCCC		3_prime_UTR	Exon 6 of 6	ENSP00000269321.7	P52565-1
	ARHGDIA	ENST00000580685.5	TSL:1	c.*61_*65dupCCCCC		3_prime_UTR	Exon 5 of 5	ENSP00000464205.1	P52565-1
	ARHGDIA	ENST00000583868.5	TSL:3	c.564_568dupCCCCC	p.Gln190ProfsTer62	frameshift	Exon 7 of 7	ENSP00000462209.1	J3KRY1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 35

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000540 Hom.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.064

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs757131763; hg19: chr17-79826686;