Variant 22-44808321-C-T details in Genebe, Genetics Data Aggregator

Variant summary

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

The ENST00000356099.11(ARHGAP8):c.182C>T(p.Thr61Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000274 in 1,461,720 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000027 ( 0 hom. )

Consequence

ARHGAP8
ENST00000356099.11 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.94

Variant links:

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]

ARHGAP8 links:

PRR5-ARHGAP8 (HGNC:):

PRR5-ARHGAP8 links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
ARHGAP8	NM_181335.3 linkuse as main transcript	c.182C>T	p.Thr61Ile	missense_variant	4/12	ENST00000356099.11	NP_851852.2
PRR5-ARHGAP8	NM_181334.6 linkuse as main transcript	c.575C>T	p.Thr192Ile	missense_variant	7/15		NP_851851.3
ARHGAP8	NM_001017526.2 linkuse as main transcript	c.182C>T	p.Thr61Ile	missense_variant	4/13		NP_001017526.1
ARHGAP8	NM_001198726.2 linkuse as main transcript	c.182C>T	p.Thr61Ile	missense_variant	4/11		NP_001185655.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ARHGAP8	ENST00000356099.11 linkuse as main transcript	c.182C>T	p.Thr61Ile	missense_variant	4/12	1	NM_181335.3	ENSP00000348407	P1	P85298-4

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000274

AC:

AN:

1461720

Hom.:

Cov.:

AF XY:

0.00000413

AC XY:

AN XY:

727168

show subpopulations

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:

0.00

Gnomad4 NFE exome

AF:

0.00000360

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 09, 2024

The c.182C>T (p.T61I) alteration is located in exon 4 (coding exon 3) of the ARHGAP8 gene. This alteration results from a C to T substitution at nucleotide position 182, causing the threonine (T) at amino acid position 61 to be replaced by an isoleucine (I). 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

0.18

BayesDel_addAF

Uncertain

0.066

BayesDel_noAF

Benign

-0.14

CADD

Benign

DANN

Benign

0.96

DEOGEN2

Benign

0.15

.;T;T;.;.;T

Eigen

Benign

-0.55

Eigen_PC

Benign

-0.66

FATHMM_MKL

Benign

0.67

LIST_S2

Uncertain

0.92

D;D;D;D;D;D

M_CAP

Benign

0.016

MetaRNN

Uncertain

0.42

T;T;T;T;T;T

MetaSVM

Benign

-0.34

MutationAssessor

Uncertain

2.5

.;M;.;M;M;.

MutationTaster

Benign

0.79

D;D;D;D;D;D;D

PrimateAI

Benign

0.39

PROVEAN

Pathogenic

-4.6

D;D;D;D;D;D

REVEL

Uncertain

0.37

Sift

Benign

0.16

T;T;T;T;T;T

Sift4G

Uncertain

0.050

T;D;T;T;T;T

Polyphen

0.98

D;P;.;.;.;.

Vest4

0.77

MutPred

0.60

Gain of ubiquitination at K190 (P = 0.0982);.;.;.;.;.;

MVP

0.39

ClinPred

0.89

GERP RS

1.0

Varity_R

0.13

gMVP

0.63

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over