17-81868633-C-A

Variant names:

• chr17-81868633-C-A
• rs189865523
• NM_004309.6:c.*243G>T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001301242.2(ARHGDIA):​c.746G>T​(p.Gly249Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000145 in 1,383,158 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 8/9 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G249E) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: ARHGDIA NM_001301242.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.728
• 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

ENSG00000262413 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.16770142).

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.*243G>T		3_prime_UTR	Exon 6 of 6	NP_004300.1	P52565-1
	ARHGDIA	NM_001301242.2		c.746G>T	p.Gly249Val	missense	Exon 7 of 7	NP_001288171.1
	ARHGDIA	NM_001301243.2		c.*243G>T		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.*243G>T		3_prime_UTR	Exon 6 of 6	ENSP00000269321.7	P52565-1
	ARHGDIA	ENST00000580685.5	TSL:1	c.*243G>T		3_prime_UTR	Exon 5 of 5	ENSP00000464205.1	P52565-1
	ARHGDIA	ENST00000583868.5	TSL:3	c.746G>T	p.Gly249Val	missense splice_region	Exon 7 of 7	ENSP00000462209.1	J3KRY1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000145 AC: 2 AN: 1383158 Hom.: 0 Cov.: 33 AF XY: 0.00000293 AC XY: 2 AN XY: 682498

African (AFR) AF: 0.00 AC: 0 AN: 31590

American (AMR) AF: 0.00 AC: 0 AN: 35690

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25168

East Asian (EAS) AF: 0.00 AC: 0 AN: 35730

South Asian (SAS) AF: 0.00 AC: 0 AN: 79138

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 33506

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5688

European-Non Finnish (NFE) AF: 0.00000185 AC: 2 AN: 1078762

Other (OTH) AF: 0.00 AC: 0 AN: 57886

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.16	T
BayesDel_noAF	Benign	-0.47
CADD	Benign	5.3
DANN	Benign	0.74
DEOGEN2	Benign	0.0052	T
FATHMM_MKL	Benign	0.65	D
LIST_S2	Benign	0.27	T
MetaRNN	Benign	0.17	T
PhyloP100		0.73
MVP		0.37
GERP RS		1.1
RBP_binding_hub_radar		0.92
RBP_regulation_power_radar		2.0

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: rs189865523; hg19: chr17-79826509;