chr6-129710070-T-C

Position:

• chr6-129710070-T-C

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_033515.3(ARHGAP18):​c.67A>G​(p.Thr23Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.853 in 1,613,836 control chromosomes in the GnomAD database, including 588,077 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/18 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.84 (53964 hom., cov: 33)
  • Exomes 𝑓: 0.85 (534113 hom.)
• Consequence: ARHGAP18 NM_033515.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.17

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 Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=8.921877E-7).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.854 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ARHGAP18	NM_033515.3	c.67A>G	p.Thr23Ala	missense_variant	1/15	ENST00000368149.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ARHGAP18	ENST00000368149.3	c.67A>G	p.Thr23Ala	missense_variant	1/15	1	NM_033515.3	P1

Frequencies

GnomAD3 genomes AF: 0.841 AC: 128022 AN: 152162 Hom.: 53922 Cov.: 33

Gnomad AFR AF: 0.825

Gnomad AMI AF: 0.888

Gnomad AMR AF: 0.852

Gnomad ASJ AF: 0.802

Gnomad EAS AF: 0.731

Gnomad SAS AF: 0.875

Gnomad FIN AF: 0.869

Gnomad MID AF: 0.826

Gnomad NFE AF: 0.853

Gnomad OTH AF: 0.823

GnomAD3 exomes AF: 0.848 AC: 213163 AN: 251280 Hom.: 90621 AF XY: 0.850 AC XY: 115408 AN XY: 135794

Gnomad AFR exome AF: 0.822

Gnomad AMR exome AF: 0.873

Gnomad ASJ exome AF: 0.801

Gnomad EAS exome AF: 0.729

Gnomad SAS exome AF: 0.883

Gnomad FIN exome AF: 0.868

Gnomad NFE exome AF: 0.856

Gnomad OTH exome AF: 0.834

GnomAD4 exome AF: 0.854 AC: 1248425 AN: 1461556 Hom.: 534113 Cov.: 56 AF XY: 0.854 AC XY: 621183 AN XY: 727098

Gnomad4 AFR exome AF: 0.814

Gnomad4 AMR exome AF: 0.872

Gnomad4 ASJ exome AF: 0.799

Gnomad4 EAS exome AF: 0.684

Gnomad4 SAS exome AF: 0.882

Gnomad4 FIN exome AF: 0.870

Gnomad4 NFE exome AF: 0.860

Gnomad4 OTH exome AF: 0.839

GnomAD4 genome AF: 0.841 AC: 128122 AN: 152280 Hom.: 53964 Cov.: 33 AF XY: 0.843 AC XY: 62760 AN XY: 74464

Gnomad4 AFR AF: 0.825

Gnomad4 AMR AF: 0.852

Gnomad4 ASJ AF: 0.802

Gnomad4 EAS AF: 0.731

Gnomad4 SAS AF: 0.876

Gnomad4 FIN AF: 0.869

Gnomad4 NFE AF: 0.853

Gnomad4 OTH AF: 0.821

Alfa AF: 0.846 Hom.: 134408

Bravo AF: 0.840

TwinsUK AF: 0.857 AC: 3178

ALSPAC AF: 0.866 AC: 3338

ESP6500AA AF: 0.827 AC: 3642

ESP6500EA AF: 0.851 AC: 7318

ExAC AF: 0.848 AC: 102906

Asia WGS AF: 0.766 AC: 2669 AN: 3478

EpiCase AF: 0.851

EpiControl AF: 0.848

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.051
BayesDel_addAF	Benign	-0.81	T
BayesDel_noAF	Benign	-0.79
CADD	Benign	17
DANN	Benign	0.80
DEOGEN2	Benign	0.018	T
Eigen	Benign	-0.45
Eigen_PC	Benign	-0.19
FATHMM_MKL	Benign	0.052	N
LIST_S2	Benign	0.17	T
MetaRNN	Benign	8.9e-7	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-1.8	N
MutationTaster	Benign	1.0	P
PrimateAI	Benign	0.36	T
Sift4G	Benign	1.0	T
Polyphen		0.0	B
Vest4		0.012
MPC		0.14
ClinPred		0.0016	T
GERP RS		5.9
Varity_R		0.041
gMVP		0.10

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

LitVar

Other links and lift over

dbSNP: rs3752536; hg19: chr6-130031215; COSMIC: COSV63763931;