chr6-129611600-C-T

Variant names:

• chr6-129611600-C-T
• rs148956917
• NM_033515.3:c.1055G>A

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The NM_033515.3(ARHGAP18):​c.1055G>A​(p.Arg352Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000181 in 1,613,408 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R352P) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00094 (1 hom., cov: 32)
  • Exomes 𝑓: 0.00010 (0 hom.)
• Consequence: ARHGAP18 NM_033515.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.09
• Publications: 2 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: Likely_benign. The variant received -4 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.011648059).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_033515.3. 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
	ARHGAP18	NM_033515.3	MANE Select	c.1055G>A	p.Arg352Gln	missense	Exon 8 of 15	NP_277050.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ARHGAP18	ENST00000368149.3	TSL:1 MANE Select	c.1055G>A	p.Arg352Gln	missense	Exon 8 of 15	ENSP00000357131.2	Q8N392-1
	ARHGAP18	ENST00000909755.1		c.968G>A	p.Arg323Gln	missense	Exon 8 of 15	ENSP00000579814.1
	ARHGAP18	ENST00000938085.1		c.787-3548G>A		intron	N/A	ENSP00000608144.1

Frequencies

GnomAD3 genomes AF: 0.000933 AC: 142 AN: 152132 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.00319

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000458

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00143

GnomAD2 exomes AF: 0.000183 AC: 46 AN: 251196 AF XY: 0.000133

Gnomad AFR exome AF: 0.00240

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000176

Gnomad OTH exome AF: 0.000653

GnomAD4 exome AF: 0.000102 AC: 149 AN: 1461158 Hom.: 0 Cov.: 30 AF XY: 0.0000935 AC XY: 68 AN XY: 726902

African (AFR) AF: 0.00320 AC: 107 AN: 33456

American (AMR) AF: 0.0000671 AC: 3 AN: 44706

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26116

East Asian (EAS) AF: 0.00 AC: 0 AN: 39600

South Asian (SAS) AF: 0.0000348 AC: 3 AN: 86224

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53342

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 0.0000162 AC: 18 AN: 1111596

Other (OTH) AF: 0.000298 AC: 18 AN: 60352

GnomAD4 genome AF: 0.000939 AC: 143 AN: 152250 Hom.: 1 Cov.: 32 AF XY: 0.000806 AC XY: 60 AN XY: 74444

African (AFR) AF: 0.00320 AC: 133 AN: 41538

American (AMR) AF: 0.000458 AC: 7 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5182

South Asian (SAS) AF: 0.00 AC: 0 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10610

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68012

Other (OTH) AF: 0.00142 AC: 3 AN: 2114

Alfa AF: 0.000257 Hom.: 0

Bravo AF: 0.00103

ESP6500AA AF: 0.00227 AC: 10

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000255 AC: 31

Asia WGS AF: 0.000289 AC: 1 AN: 3478

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	0.074
BayesDel_addAF	Benign	-0.53	T
BayesDel_noAF	Benign	-0.54
CADD	Benign	18
DANN	Benign	0.96
DEOGEN2	Benign	0.025	T
Eigen	Benign	-0.73
Eigen_PC	Benign	-0.56
FATHMM_MKL	Benign	0.61	D
LIST_S2	Benign	0.85	D
M_CAP	Benign	0.013	T
MetaRNN	Benign	0.012	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-0.34	N
PhyloP100		2.1
PrimateAI	Benign	0.26	T
REVEL	Benign	0.081
Sift4G	Benign	0.40	T
Polyphen		0.032	B
Vest4		0.28
MVP		0.44
MPC		0.17
ClinPred		0.013	T
GERP RS		2.9
Varity_R		0.024
gMVP		0.20
Mutation Taster		=96/4	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs148956917; hg19: chr6-129932745;