6-129616286-C-T

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BP4_Moderate BP6_Moderate

The NM_033515.3(ARHGAP18):c.970G>A(p.Val324Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000331 in 1,608,406 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.00024 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00034 (3 hom.)
• Consequence: ARHGAP18 NM_033515.3 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 1.58

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 Likely_benign. Variant got -4 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.12098223).
• BP6: Variant 6-129616286-C-T is Benign according to our data. Variant chr6-129616286-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 2353583.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ARHGAP18	NM_033515.3	c.970G>A	p.Val324Ile	missense_variant	7/15	ENST00000368149.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ARHGAP18	ENST00000368149.3	c.970G>A	p.Val324Ile	missense_variant	7/15	1	NM_033515.3	P1

Frequencies

GnomAD3 genomes AF: 0.000237 AC: 36 AN: 151896 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000290

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0000951

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000309

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000184 AC: 46 AN: 250248 Hom.: 0 AF XY: 0.000177 AC XY: 24 AN XY: 135306

Gnomad AFR exome AF: 0.000370

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000548

Gnomad SAS exome AF: 0.0000986

Gnomad FIN exome AF: 0.0000463

Gnomad NFE exome AF: 0.000309

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000341 AC: 496 AN: 1456394 Hom.: 3 Cov.: 30 AF XY: 0.000322 AC XY: 233 AN XY: 724330

Gnomad4 AFR exome AF: 0.000240

Gnomad4 AMR exome AF: 0.0000451

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000101

Gnomad4 SAS exome AF: 0.0000472

Gnomad4 FIN exome AF: 0.0000754

Gnomad4 NFE exome AF: 0.000410

Gnomad4 OTH exome AF: 0.000316

GnomAD4 genome AF: 0.000237 AC: 36 AN: 152012 Hom.: 0 Cov.: 32 AF XY: 0.000188 AC XY: 14 AN XY: 74304

Gnomad4 AFR AF: 0.000289

Gnomad4 AMR AF: 0.000131

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.0000951

Gnomad4 NFE AF: 0.000309

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000309 Hom.: 0

Bravo AF: 0.000268

TwinsUK AF: 0.00108 AC: 4

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000465 AC: 4

ExAC AF: 0.000214 AC: 26

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 16, 2021

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.074
BayesDel_addAF	Benign	-0.45	T
BayesDel_noAF	Benign	-0.53
Cadd	Benign	10
Dann	Benign	0.89
DEOGEN2	Benign	0.10	T
Eigen	Benign	-0.70
Eigen_PC	Benign	-0.66
FATHMM_MKL	Uncertain	0.85	D
LIST_S2	Benign	0.78	T
M_CAP	Benign	0.015	T
MetaRNN	Benign	0.12	T
MetaSVM	Benign	-0.97	T
MutationAssessor	Uncertain	2.4	M
MutationTaster	Benign	0.98	D;D
PrimateAI	Benign	0.25	T
REVEL	Benign	0.089
Sift4G	Benign	0.11	T
Polyphen		0.068	B
Vest4		0.19
MVP		0.64
MPC		0.14
ClinPred		0.034	T
GERP RS		0.68
Varity_R		0.027
gMVP		0.31

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

Publications

LitVar

Other links and lift over

dbSNP: rs151200685; hg19: chr6-129937431; COSMIC: COSV63764229;