22-44822385-A-G

Position:

• chr22-44822385-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_181335.3(ARHGAP8):​c.401A>G​(p.Lys134Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000028 in 1,429,374 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000028 (0 hom.)
• Consequence: ARHGAP8 NM_181335.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.46

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]

ARHGAP8 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.079734534).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ARHGAP8	NM_181335.3	c.401A>G	p.Lys134Arg	missense_variant	6/12	ENST00000356099.11	NP_851852.2
PRR5-ARHGAP8	NM_181334.6	c.794A>G	p.Lys265Arg	missense_variant	9/15		NP_851851.3
ARHGAP8	NM_001017526.2	c.494A>G	p.Lys165Arg	missense_variant	7/13		NP_001017526.1
ARHGAP8	NM_001198726.2	c.401A>G	p.Lys134Arg	missense_variant	6/11		NP_001185655.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ARHGAP8	ENST00000356099.11	c.401A>G	p.Lys134Arg	missense_variant	6/12	1	NM_181335.3	ENSP00000348407.6
PRR5-ARHGAP8	ENST00000352766.11	c.1031A>G	p.Lys344Arg	missense_variant	11/17	2		ENSP00000262731.11

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.0000138 AC: 3 AN: 216968 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 118034

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000471

Gnomad NFE exome AF: 0.0000197

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000280 AC: 4 AN: 1429374 Hom.: 0 Cov.: 32 AF XY: 0.00000141 AC XY: 1 AN XY: 710384

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.0000188

Gnomad4 NFE exome AF: 0.00000273

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000378

ExAC AF: 0.0000247 AC: 3

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

Oct 10, 2023

The c.494A>G (p.K165R) alteration is located in exon 7 (coding exon 6) of the ARHGAP8 gene. This alteration results from a A to G substitution at nucleotide position 494, causing the lysine (K) at amino acid position 165 to be replaced by an arginine (R). 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	0.077
BayesDel_addAF	Benign	-0.15	T
BayesDel_noAF	Benign	-0.43
CADD	Benign	18
DANN	Benign	0.69
DEOGEN2	Benign	0.027	.;.;T;.;.
Eigen	Benign	-0.17
Eigen_PC	Benign	-0.12
FATHMM_MKL	Benign	0.69	D
LIST_S2	Benign	0.81	T;T;T;T;T
M_CAP	Benign	0.0065	T
MetaRNN	Benign	0.080	T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.83	.;.;L;.;.
PrimateAI	Benign	0.42	T
PROVEAN	Benign	0.16	N;N;N;N;N
REVEL	Benign	0.077
Sift	Benign	0.79	T;T;T;T;T
Sift4G	Benign	0.86	T;T;T;T;T
Polyphen		0.065	B;B;B;.;.
Vest4		0.21
MutPred		0.46		.;Loss of methylation at K344 (P = 0.0182);.;.;.;
MVP		0.12
ClinPred		0.32	T
GERP RS		3.2
Varity_R		0.031
gMVP		0.32

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: rs756279477; hg19: chr22-45218265;