6-129710070-T-C

Variant names:

• chr6-129710070-T-C
• rs3752536
• NM_033515.3:c.67A>G

Variant summary

Our verdict is Benign. The variant received -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. 13/19 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 variant affecting the same amino acid position, but resulting in a different missense (i.e. T23I) has been classified as Uncertain significance.

• 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
• Publications: 39 publications found

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

Our verdict: Benign. The variant received -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 rank	MANE	Protein	UniProt
ARHGAP18	NM_033515.3	c.67A>G	p.Thr23Ala	missense_variant	Exon 1 of 15	ENST00000368149.3	NP_277050.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ARHGAP18	ENST00000368149.3	c.67A>G	p.Thr23Ala	missense_variant	Exon 1 of 15	1	NM_033515.3	ENSP00000357131.2

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

GnomAD2 exomes AF: 0.848 AC: 213163 AN: 251280 AF XY: 0.850

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 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

African (AFR) AF: 0.814 AC: 27245 AN: 33476

American (AMR) AF: 0.872 AC: 38971 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.799 AC: 20870 AN: 26124

East Asian (EAS) AF: 0.684 AC: 27167 AN: 39690

South Asian (SAS) AF: 0.882 AC: 76039 AN: 86232

European-Finnish (FIN) AF: 0.870 AC: 46460 AN: 53406

Middle Eastern (MID) AF: 0.816 AC: 4700 AN: 5758

European-Non Finnish (NFE) AF: 0.860 AC: 956336 AN: 1111778

Other (OTH) AF: 0.839 AC: 50637 AN: 60376

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

African (AFR) AF: 0.825 AC: 34290 AN: 41566

American (AMR) AF: 0.852 AC: 13041 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.802 AC: 2782 AN: 3470

East Asian (EAS) AF: 0.731 AC: 3773 AN: 5164

South Asian (SAS) AF: 0.876 AC: 4230 AN: 4830

European-Finnish (FIN) AF: 0.869 AC: 9220 AN: 10616

Middle Eastern (MID) AF: 0.827 AC: 243 AN: 294

European-Non Finnish (NFE) AF: 0.853 AC: 58005 AN: 68016

Other (OTH) AF: 0.821 AC: 1732 AN: 2110

Alfa AF: 0.845 Hom.: 191584

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
PhyloP100		2.2
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
PromoterAI		0.049	Neutral
Varity_R		0.041
gMVP		0.10
Mutation Taster		=98/2	polymorphism (auto)

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

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