22-44822451-T-C

Position:

• chr22-44822451-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The ENST00000356099.11(ARHGAP8):​c.467T>C​(p.Ile156Thr) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: ARHGAP8 ENST00000356099.11 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.42

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 Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.38690513).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ARHGAP8	NM_181335.3	c.467T>C	p.Ile156Thr	missense_variant	6/12	ENST00000356099.11	NP_851852.2
PRR5-ARHGAP8	NM_181334.6	c.860T>C	p.Ile287Thr	missense_variant	9/15		NP_851851.3
ARHGAP8	NM_001017526.2	c.560T>C	p.Ile187Thr	missense_variant	7/13		NP_001017526.1
ARHGAP8	NM_001198726.2	c.467T>C	p.Ile156Thr	missense_variant	6/11		NP_001185655.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ARHGAP8	ENST00000356099.11	c.467T>C	p.Ile156Thr	missense_variant	6/12	1	NM_181335.3	ENSP00000348407	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

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

Jan 31, 2023

The c.560T>C (p.I187T) alteration is located in exon 7 (coding exon 6) of the ARHGAP8 gene. This alteration results from a T to C substitution at nucleotide position 560, causing the isoleucine (I) at amino acid position 187 to be replaced by a threonine (T). 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	Pathogenic	0.65
BayesDel_addAF	Uncertain	0.088	D
BayesDel_noAF	Benign	-0.11
CADD	Benign	21
DANN	Uncertain	0.99
DEOGEN2	Benign	0.25	.;.;T;.;.
Eigen	Benign	0.042
Eigen_PC	Benign	-0.0029
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Uncertain	0.91	D;D;D;D;D
M_CAP	Benign	0.049	D
MetaRNN	Benign	0.39	T;T;T;T;T
MetaSVM	Benign	-0.60	T
MutationAssessor	Pathogenic	3.5	.;.;H;.;.
MutationTaster	Benign	0.93	D;D;D;D;D;D;D
PrimateAI	Benign	0.45	T
PROVEAN	Uncertain	-4.0	D;D;D;D;D
REVEL	Uncertain	0.39
Sift	Uncertain	0.0010	D;D;D;D;D
Sift4G	Benign	0.077	T;D;D;D;D
Polyphen		0.99	D;P;D;.;.
Vest4		0.57
MutPred		0.48		.;Loss of catalytic residue at L371 (P = 0.0273);.;.;.;
MVP		0.47
ClinPred		0.99	D
GERP RS		4.3
Varity_R		0.29
gMVP		0.64

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr22-45218331;