chr22-44808321-C-T

Variant names:

• chr22-44808321-C-T
• NM_181335.3:c.182C>T

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_181335.3(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 NM_181335.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.94
• Publications: 0 publications found

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]

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_181335.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ARHGAP8	NM_181335.3	MANE Select	c.182C>T	p.Thr61Ile	missense	Exon 4 of 12	NP_851852.2	P85298-4
	PRR5-ARHGAP8	NM_181334.6		c.575C>T	p.Thr192Ile	missense	Exon 7 of 15	NP_851851.3	B1AHC3
	ARHGAP8	NM_001017526.2		c.182C>T	p.Thr61Ile	missense	Exon 4 of 13	NP_001017526.1	P85298-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ARHGAP8	ENST00000356099.11	TSL:1 MANE Select	c.182C>T	p.Thr61Ile	missense	Exon 4 of 12	ENSP00000348407.6	P85298-4
	ARHGAP8	ENST00000336963.8	TSL:1	c.182C>T	p.Thr61Ile	missense	Exon 4 of 11	ENSP00000337287.4	P85298-5
	PRR5-ARHGAP8	ENST00000352766.11	TSL:2	c.929+6157C>T		intron	N/A	ENSP00000262731.11	B1AHC4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000274 AC: 4 AN: 1461720 Hom.: 0 Cov.: 31 AF XY: 0.00000413 AC XY: 3 AN XY: 727168

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44702

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26118

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.00 AC: 0 AN: 86240

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53412

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00000360 AC: 4 AN: 1111914

Other (OTH) AF: 0.00 AC: 0 AN: 60388

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.18
BayesDel_addAF	Uncertain	0.066	T
BayesDel_noAF	Benign	-0.14
CADD	Benign	15
DANN	Benign	0.96
DEOGEN2	Benign	0.15	T
Eigen	Benign	-0.55
Eigen_PC	Benign	-0.66
FATHMM_MKL	Benign	0.67	D
LIST_S2	Uncertain	0.92	D
M_CAP	Benign	0.016	T
MetaRNN	Uncertain	0.42	T
MetaSVM	Benign	-0.34	T
MutationAssessor	Uncertain	2.5	M
PhyloP100		1.9
PrimateAI	Benign	0.39	T
PROVEAN	Pathogenic	-4.6	D
REVEL	Uncertain	0.37
Sift	Benign	0.16	T
Sift4G	Uncertain	0.050	T
Polyphen		0.98	D
Vest4		0.77
MutPred		0.60		Gain of ubiquitination at K190 (P = 0.0982)
MVP		0.39
ClinPred		0.89	D
GERP RS		1.0
Varity_R		0.13
gMVP		0.63
Mutation Taster		=70/30	polymorphism

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

Other links and lift over

hg19: chr22-45204201;