22-44754779-C-T

Variant names:

• chr22-44754779-C-T
• rs5765956
• NM_181335.3:c.-72+2152C>T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_181335.3(ARHGAP8):​c.-72+2152C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.498 in 151,876 control chromosomes in the GnomAD database, including 19,328 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.50 (19328 hom., cov: 31)
• Consequence: ARHGAP8 NM_181335.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.218
• Publications: 11 publications found

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]

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.89).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.541 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ARHGAP8	NM_181335.3	c.-72+2152C>T		intron_variant	Intron 1 of 11	ENST00000356099.11	NP_851852.2
PRR5-ARHGAP8	NM_181334.6	c.322+28145C>T		intron_variant	Intron 4 of 14		NP_851851.3
ARHGAP8	NM_001017526.2	c.-72+2152C>T		intron_variant	Intron 1 of 12		NP_001017526.1
ARHGAP8	NM_001198726.2	c.-72+2152C>T		intron_variant	Intron 1 of 10		NP_001185655.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ARHGAP8	ENST00000356099.11	c.-72+2152C>T		intron_variant	Intron 1 of 11	1	NM_181335.3	ENSP00000348407.6
PRR5-ARHGAP8	ENST00000352766.11	c.691+19617C>T		intron_variant	Intron 7 of 16	2		ENSP00000262731.11

Frequencies

GnomAD3 genomes AF: 0.498 AC: 75592 AN: 151758 Hom.: 19319 Cov.: 31

Gnomad AFR AF: 0.432

Gnomad AMI AF: 0.688

Gnomad AMR AF: 0.443

Gnomad ASJ AF: 0.518

Gnomad EAS AF: 0.528

Gnomad SAS AF: 0.315

Gnomad FIN AF: 0.579

Gnomad MID AF: 0.472

Gnomad NFE AF: 0.545

Gnomad OTH AF: 0.504

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.498 AC: 75630 AN: 151876 Hom.: 19328 Cov.: 31 AF XY: 0.494 AC XY: 36657 AN XY: 74204

African (AFR) AF: 0.432 AC: 17877 AN: 41406

American (AMR) AF: 0.442 AC: 6742 AN: 15244

Ashkenazi Jewish (ASJ) AF: 0.518 AC: 1799 AN: 3470

East Asian (EAS) AF: 0.527 AC: 2719 AN: 5160

South Asian (SAS) AF: 0.315 AC: 1513 AN: 4806

European-Finnish (FIN) AF: 0.579 AC: 6103 AN: 10546

Middle Eastern (MID) AF: 0.490 AC: 144 AN: 294

European-Non Finnish (NFE) AF: 0.545 AC: 37047 AN: 67930

Other (OTH) AF: 0.502 AC: 1060 AN: 2110

Alfa AF: 0.529 Hom.: 73508

Bravo AF: 0.490

Asia WGS AF: 0.438 AC: 1519 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	0.95
DANN	Benign	0.73
PhyloP100		-0.22
Mutation Taster		=100/0	polymorphism (auto)

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: rs5765956; hg19: chr22-45150659;