chr6-129605887-T-C

Position:

• chr6-129605887-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_033515.3(ARHGAP18):​c.1355A>G​(p.Asp452Gly) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 32)
• Consequence: ARHGAP18 NM_033515.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.88

Genes affected

ARHGAP18 (HGNC:21035): (Rho GTPase activating protein 18) Enables GTPase activator activity. Involved in several processes, including regulation of actin filament polymerization; regulation of small GTPase mediated signal transduction; and small GTPase mediated signal transduction. Located in cytosol; nuclear speck; and plasma membrane. Part of cytoplasmic microtubule and ruffle. Implicated in schizophrenia. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.854

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ARHGAP18	NM_033515.3	c.1355A>G	p.Asp452Gly	missense_variant	10/15	ENST00000368149.3	NP_277050.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ARHGAP18	ENST00000368149.3	c.1355A>G	p.Asp452Gly	missense_variant	10/15	1	NM_033515.3	ENSP00000357131.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

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

Dec 03, 2024

The c.1355A>G (p.D452G) alteration is located in exon 10 (coding exon 10) of the ARHGAP18 gene. This alteration results from a A to G substitution at nucleotide position 1355, causing the aspartic acid (D) at amino acid position 452 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	0.24
BayesDel_addAF	Pathogenic	0.24	D
BayesDel_noAF	Uncertain	0.10
CADD	Pathogenic	29
DANN	Uncertain	1.0
DEOGEN2	Benign	0.23	T
Eigen	Uncertain	0.62
Eigen_PC	Uncertain	0.55
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.94	D
M_CAP	Benign	0.048	D
MetaRNN	Pathogenic	0.85	D
MetaSVM	Uncertain	-0.13	T
MutationAssessor	Pathogenic	3.1	M
PrimateAI	Uncertain	0.55	T
REVEL	Pathogenic	0.85
Sift4G	Uncertain	0.014	D
Polyphen		0.97	D
Vest4		0.74
MutPred		0.65		Loss of stability (P = 0.0145);
MVP		0.69
MPC		0.50
ClinPred		0.98	D
GERP RS		5.3
Varity_R		0.57
gMVP		0.61

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.13		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: chr6-129927032;