NM_004309.6:c.*65_*66insCCCCCCCCCCCCCCCCCC

Variant names:

• chr17-81868810-T-TGGGGGGGGGGGGGGGGGG
• rs757131763
• NM_004309.6:c.*65_*66insCCCCCCCCCCCCCCCCCC

Variant summary

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

The NM_004309.6(ARHGDIA):​c.*65_*66insCCCCCCCCCCCCCCCCCC variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000252 in 396,952 control chromosomes in the GnomAD database, with no homozygous occurrence. It is difficult to determine the true allele frequency of this variant because it is of type INS_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000025 (0 hom.)
• 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 0 ACMG points.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ARHGDIA	NM_004309.6	c.*65_*66insCCCCCCCCCCCCCCCCCC		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.*65_*66insCCCCCCCCCCCCCCCCCC		3_prime_UTR_variant	Exon 6 of 6	1	NM_004309.6	ENSP00000269321.7

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000252 AC: 1 AN: 396952 Hom.: 0 Cov.: 35 AF XY: 0.00 AC XY: 0 AN XY: 216822

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

African (AFR) AF: 0.00 AC: 0 AN: 11504

American (AMR) AF: 0.00 AC: 0 AN: 29106

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 11658

South Asian (SAS) AF: 0.00 AC: 0 AN: 49560

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 24972

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2704

European-Non Finnish (NFE) AF: 0.00000416 AC: 1 AN: 240300

Other (OTH) AF: 0.00 AC: 0 AN: 16562

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

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;