22-44809096-C-T

Position:

• chr22-44809096-C-T

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 2P and 7B. PM2 BP4_Strong BP6_Moderate BP7

The NM_001017526.2(ARHGAP8):​c.390C>T​(p.Tyr130Tyr) variant causes a splice region, synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000853 in 470,348 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.00093 (0 hom., cov: 31)
  • Exomes 𝑓: 0.00081 (1 hom.)
• Consequence: ARHGAP8 NM_001017526.2 splice_region, synonymous
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.379

Genes affected

ARHGAP8 (HGNC:677): (Rho GTPase activating protein 8) This gene encodes a member of the RHOGAP family. GAP (GTPase-activating) family proteins participate in signaling pathways that regulate cell processes involved in cytoskeletal changes. GAP proteins alternate between an active (GTP-bound) and inactive (GDP-bound) state based on the GTP:GDP ratio in the cell. This family member is a multidomain protein that functions to promote Erk activation and cell motility. Alternative splicing results in multiple transcript variants. Read-through transcripts from the upstream proline rich 5, renal (PRR5) gene into this gene also exist, which led to the original description of PRR5 and ARHGAP8 being a single gene. [provided by RefSeq, Nov 2010]

PRR5-ARHGAP8 (HGNC:34512): (PRR5-ARHGAP8 readthrough) The PRR5-ARHGAP8 mRNA is an infrequent but naturally occurring read-through transcript of the neighboring proline rich 5, renal (PRR5) and Rho GTPase activating protein 8 (ARHGAP8) genes. The resulting fusion protein contains sequence identity with each individual gene product, and it includes domains characteristic of a RhoGAP protein. The significance of this read-through transcript and the function of its protein product have not yet been determined. [provided by RefSeq, Nov 2010]

PRR5-ARHGAP8 (HGNC:):

ACMG classification

Verdict is Likely_benign. Variant got -5 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.97).
• BP6: Variant 22-44809096-C-T is Benign according to our data. Variant chr22-44809096-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 2653278.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=0.379 with no splicing effect.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ARHGAP8	NM_181335.3	c.299+658C>T		intron_variant		ENST00000356099.11	NP_851852.2
ARHGAP8	NM_001017526.2	c.390C>T	p.Tyr130Tyr	splice_region_variant, synonymous_variant	5/13		NP_001017526.1
PRR5-ARHGAP8	NM_181334.6	c.692+658C>T		intron_variant			NP_851851.3
ARHGAP8	NM_001198726.2	c.299+658C>T		intron_variant			NP_001185655.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ARHGAP8	ENST00000356099.11	c.299+658C>T		intron_variant		1	NM_181335.3	ENSP00000348407.6
PRR5-ARHGAP8	ENST00000352766.11	c.930-5576C>T		intron_variant		2		ENSP00000262731.11

Frequencies

GnomAD3 genomes AF: 0.000934 AC: 142 AN: 152086 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.000217

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00177

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0000942

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.00150

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.000743 AC: 110 AN: 148080 Hom.: 1 AF XY: 0.000676 AC XY: 54 AN XY: 79824

Gnomad AFR exome AF: 0.000148

Gnomad AMR exome AF: 0.000651

Gnomad ASJ exome AF: 0.000359

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000355

Gnomad FIN exome AF: 0.0000618

Gnomad NFE exome AF: 0.00141

Gnomad OTH exome AF: 0.000931

GnomAD4 exome AF: 0.000814 AC: 259 AN: 318144 Hom.: 1 Cov.: 0 AF XY: 0.000851 AC XY: 153 AN XY: 179820

Gnomad4 AFR exome AF: 0.000116

Gnomad4 AMR exome AF: 0.000623

Gnomad4 ASJ exome AF: 0.000185

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000486

Gnomad4 FIN exome AF: 0.000150

Gnomad4 NFE exome AF: 0.00118

Gnomad4 OTH exome AF: 0.00105

GnomAD4 genome AF: 0.000933 AC: 142 AN: 152204 Hom.: 0 Cov.: 31 AF XY: 0.00105 AC XY: 78 AN XY: 74412

Gnomad4 AFR AF: 0.000217

Gnomad4 AMR AF: 0.00177

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.0000942

Gnomad4 NFE AF: 0.00150

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.00101 Hom.: 1

Bravo AF: 0.000805

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Aug 01, 2022

ARHGAP8: BP4, BP7 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.97
CADD	Benign	7.9
DANN	Benign	0.58

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

Publications

LitVar

Other links and lift over

dbSNP: rs559051849; hg19: chr22-45204976;