22-44822468-C-G

Position:

• chr22-44822468-C-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.484C>G​(p.Arg162Gly) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000715 in 1,397,814 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 7.2e-7 (0 hom.)
• Consequence: ARHGAP8 NM_181335.3 missense, splice_region
• Scores: Splicing: ADA: 0.004073
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.584

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=0.2232661).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ARHGAP8	NM_181335.3	c.484C>G	p.Arg162Gly	missense_variant, splice_region_variant	6/12	ENST00000356099.11	NP_851852.2
PRR5-ARHGAP8	NM_181334.6	c.877C>G	p.Arg293Gly	missense_variant, splice_region_variant	9/15		NP_851851.3
ARHGAP8	NM_001017526.2	c.577C>G	p.Arg193Gly	missense_variant, splice_region_variant	7/13		NP_001017526.1
ARHGAP8	NM_001198726.2	c.484C>G	p.Arg162Gly	missense_variant, splice_region_variant	6/11		NP_001185655.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ARHGAP8	ENST00000356099.11	c.484C>G	p.Arg162Gly	missense_variant, splice_region_variant	6/12	1	NM_181335.3	ENSP00000348407.6
PRR5-ARHGAP8	ENST00000352766.11	c.1114C>G	p.Arg372Gly	missense_variant, splice_region_variant	11/17	2		ENSP00000262731.11

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 7.15e-7 AC: 1 AN: 1397814 Hom.: 0 Cov.: 32 AF XY: 0.00000144 AC XY: 1 AN XY: 693576

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: 0.0000134

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

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

Aug 20, 2023

The c.577C>G (p.R193G) alteration is located in exon 7 (coding exon 6) of the ARHGAP8 gene. This alteration results from a C to G substitution at nucleotide position 577, causing the arginine (R) at amino acid position 193 to be replaced by a glycine (G). 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	0.15
BayesDel_addAF	Uncertain	0.068	T
BayesDel_noAF	Benign	-0.14
CADD	Benign	23
DANN	Uncertain	0.99
DEOGEN2	Benign	0.13	.;.;T;.;.
Eigen	Benign	-0.22
Eigen_PC	Benign	-0.29
FATHMM_MKL	Benign	0.33	N
LIST_S2	Benign	0.84	T;D;D;T;T
M_CAP	Uncertain	0.086	D
MetaRNN	Benign	0.22	T;T;T;T;T
MetaSVM	Benign	-0.65	T
MutationAssessor	Uncertain	2.2	.;.;M;.;.
PrimateAI	Benign	0.30	T
PROVEAN	Uncertain	-2.8	D;D;D;D;D
REVEL	Benign	0.24
Sift	Benign	0.075	T;T;T;D;D
Sift4G	Benign	0.17	T;T;T;T;T
Polyphen		0.91	P;D;P;.;.
Vest4		0.39
MutPred		0.45		.;Loss of solvent accessibility (P = 0.0509);.;.;.;
MVP		0.57
ClinPred		0.88	D
GERP RS		3.1
Varity_R		0.13
gMVP		0.62

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.0041
dbscSNV1_RF	Benign	0.040
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

No publications associated with this variant yet.

Other links and lift over

hg19: chr22-45218348;