22-44808383-C-T

Position:

• chr22-44808383-C-T

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The ENST00000356099.11(ARHGAP8):​c.244C>T​(p.Arg82Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000929 in 1,614,236 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00048 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000053 (0 hom.)
• Consequence: ARHGAP8 ENST00000356099.11 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.0410

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:):

ACMG classification

Verdict is Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.013684303).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ARHGAP8	NM_181335.3	c.244C>T	p.Arg82Trp	missense_variant	4/12	ENST00000356099.11	NP_851852.2
PRR5-ARHGAP8	NM_181334.6	c.637C>T	p.Arg213Trp	missense_variant	7/15		NP_851851.3
ARHGAP8	NM_001017526.2	c.244C>T	p.Arg82Trp	missense_variant	4/13		NP_001017526.1
ARHGAP8	NM_001198726.2	c.244C>T	p.Arg82Trp	missense_variant	4/11		NP_001185655.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ARHGAP8	ENST00000356099.11	c.244C>T	p.Arg82Trp	missense_variant	4/12	1	NM_181335.3	ENSP00000348407	P1

Frequencies

GnomAD3 genomes AF: 0.000460 AC: 70 AN: 152234 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00147

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.000620

Gnomad FIN AF: 0.000188

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000121 AC: 30 AN: 248932 Hom.: 0 AF XY: 0.0000668 AC XY: 9 AN XY: 134776

Gnomad AFR exome AF: 0.00129

Gnomad AMR exome AF: 0.0000578

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000163

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.000139

Gnomad NFE exome AF: 0.00000899

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000527 AC: 77 AN: 1461884 Hom.: 0 Cov.: 31 AF XY: 0.0000468 AC XY: 34 AN XY: 727242

Gnomad4 AFR exome AF: 0.00122

Gnomad4 AMR exome AF: 0.0000894

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.0000464

Gnomad4 FIN exome AF: 0.000225

Gnomad4 NFE exome AF: 0.00000629

Gnomad4 OTH exome AF: 0.000132

GnomAD4 genome AF: 0.000479 AC: 73 AN: 152352 Hom.: 0 Cov.: 32 AF XY: 0.000523 AC XY: 39 AN XY: 74502

Gnomad4 AFR AF: 0.00154

Gnomad4 AMR AF: 0.000131

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.000621

Gnomad4 FIN AF: 0.000188

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000869 Hom.: 0

Bravo AF: 0.000385

ESP6500AA AF: 0.000908 AC: 4

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000123 AC: 15

Asia WGS AF: 0.000578 AC: 2 AN: 3476

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 08, 2022

The c.610C>T (p.R204W) alteration is located in exon 7 (coding exon 7) of the PRR5-ARHGAP8 gene. This alteration results from a C to T substitution at nucleotide position 610, causing the arginine (R) at amino acid position 204 to be replaced by a tryptophan (W). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.45	T
BayesDel_noAF	Benign	-0.43
CADD	Benign	23
DANN	Uncertain	0.98
DEOGEN2	Benign	0.29	.;T;T;.;.;T
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.056	N
LIST_S2	Benign	0.48	T;T;T;T;T;T
M_CAP	Benign	0.0038	T
MetaRNN	Benign	0.014	T;T;T;T;T;T
MetaSVM	Benign	-0.96	T
MutationAssessor	Benign	1.6	.;L;.;L;L;.
MutationTaster	Benign	0.68	D;N;N;N;N;D;N
PrimateAI	Benign	0.24	T
PROVEAN	Uncertain	-3.5	D;D;D;D;D;D
REVEL	Benign	0.11
Sift	Uncertain	0.022	D;D;D;D;D;D
Sift4G	Uncertain	0.013	D;D;D;D;D;D
Polyphen		0.14	B;B;.;.;.;.
Vest4		0.30
MVP		0.37
ClinPred		0.038	T
GERP RS		-2.0
Varity_R		0.11
gMVP		0.35

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: rs6007304; hg19: chr22-45204263; COSMIC: COSV61231840;