17-81868708-A-G

Variant names:

• chr17-81868708-A-G
• rs754414636
• NM_004309.6:c.*168T>C

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4_Strong BP6

The NM_004309.6(ARHGDIA):​c.*168T>C variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000123 in 1,440,564 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (no stars).

• Frequency:
  • Genomes: 𝑓 0.00075 (0 hom., cov: 31)
  • Exomes 𝑓: 0.000063 (0 hom.)
• Consequence: ARHGDIA NM_004309.6 3_prime_UTR
• Clinical Significance: Likely benign no assertion criteria provided B:1
• Conservation: PhyloP100: -0.221
• 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

ENSG00000262413 (HGNC:):

ACMG classification

Our verdict: Likely_benign. The variant received -5 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0064575076).
• BP6: Variant 17-81868708-A-G is Benign according to our data. Variant chr17-81868708-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 3051366.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ARHGDIA	NM_004309.6	c.*168T>C		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.*168T>C		3_prime_UTR_variant	Exon 6 of 6	1	NM_004309.6	ENSP00000269321.7

Frequencies

GnomAD3 genomes AF: 0.000733 AC: 92 AN: 125582 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.00271

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000169

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: 0.000581

GnomAD2 exomes AF: 0.0000846 AC: 11 AN: 130042 AF XY: 0.0000562

Gnomad AFR exome AF: 0.00114

Gnomad AMR exome AF: 0.000165

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000631 AC: 83 AN: 1314884 Hom.: 0 Cov.: 33 AF XY: 0.0000525 AC XY: 34 AN XY: 648022

African (AFR) AF: 0.00220 AC: 65 AN: 29562

American (AMR) AF: 0.000209 AC: 7 AN: 33484

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 22548

East Asian (EAS) AF: 0.00 AC: 0 AN: 30204

South Asian (SAS) AF: 0.00 AC: 0 AN: 77576

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 28120

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4954

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1035188

Other (OTH) AF: 0.000207 AC: 11 AN: 53248

GnomAD4 genome AF: 0.000748 AC: 94 AN: 125680 Hom.: 0 Cov.: 31 AF XY: 0.000730 AC XY: 44 AN XY: 60264

African (AFR) AF: 0.00276 AC: 91 AN: 32966

American (AMR) AF: 0.000169 AC: 2 AN: 11856

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3170

East Asian (EAS) AF: 0.00 AC: 0 AN: 4050

South Asian (SAS) AF: 0.00 AC: 0 AN: 3708

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 7200

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 240

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 59982

Other (OTH) AF: 0.000575 AC: 1 AN: 1738

Alfa AF: 0.0000868 Hom.: 0

Bravo AF: 0.000748

ExAC AF: 0.0000489 AC: 3

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: no assertion criteria provided

Submissions by phenotype

ARHGDIA-related disorder Benign:1

Feb 13, 2022

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.53	T
BayesDel_noAF	Benign	-0.54
CADD	Benign	1.2
DANN	Benign	0.16
DEOGEN2	Benign	0.0063	T
FATHMM_MKL	Benign	0.029	N
LIST_S2	Benign	0.18	T
MetaRNN	Benign	0.0065	T
PhyloP100		-0.22
MVP		0.22
GERP RS		-1.0

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: rs754414636; hg19: chr17-79826584;