chr17-81868810-T-TGGG

Variant names:

• chr17-81868810-T-TGGG
• rs757131763
• NM_004309.6:c.*63_*65dupCCC

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_004309.6(ARHGDIA):​c.*63_*65dupCCC variant causes a 3 prime UTR 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: 𝑓 0.000024 (0 hom., cov: 32)
  • Failed GnomAD Quality Control
• Consequence: ARHGDIA NM_004309.6 3_prime_UTR
• 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: Ambry Genetics, Labcorp Genetics (formerly Invitae)
• familial idiopathic steroid-resistant nephrotic syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ARHGDIA	NM_004309.6	c.*63_*65dupCCC		3_prime_UTR_variant	Exon 6 of 6	ENST00000269321.12	NP_004300.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ARHGDIA	ENST00000269321.12	c.*63_*65dupCCC		3_prime_UTR_variant	Exon 6 of 6	1	NM_004309.6	ENSP00000269321.7

Frequencies

GnomAD3 genomes AF: 0.0000244 AC: 1 AN: 40914 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000950

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome Cov.: 35

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.0000244 AC: 1 AN: 40974 Hom.: 0 Cov.: 32 AF XY: 0.0000494 AC XY: 1 AN XY: 20250

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

African (AFR) AF: 0.0000946 AC: 1 AN: 10570

American (AMR) AF: 0.00 AC: 0 AN: 3810

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 2014

South Asian (SAS) AF: 0.00 AC: 0 AN: 1354

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 2084

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

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 19214

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

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.064
Mutation Taster		=100/0	polymorphism

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;