19-7372830-C-T

Variant names:

• chr19-7372830-C-T
• rs140250213
• NM_001367823.1:c.34C>T

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4_Strong BS1_Supporting

The NM_001367823.1(ARHGEF18):​c.34C>T​(p.Arg12Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000454 in 1,234,458 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 8/10 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00047 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00045 (1 hom.)
• Consequence: ARHGEF18 NM_001367823.1 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.441
• Publications: 0 publications found

Genes affected

ARHGEF18 (HGNC:17090): (Rho/Rac guanine nucleotide exchange factor 18) Rho GTPases are GTP binding proteins that regulate a wide spectrum of cellular functions. These cellular processes include cytoskeletal rearrangements, gene transcription, cell growth and motility. Activation of Rho GTPases is under the direct control of guanine nucleotide exchange factors (GEFs). The protein encoded by this gene is a guanine nucleotide exchange factor and belongs to the Rho GTPase GEF family. Family members share a common feature, a Dbl (DH) homology domain followed by a pleckstrin (PH) homology domain. Alternatively spliced transcript variants encoding different isoforms have been identified. [provided by RefSeq, Nov 2018]

ARHGEF18-AS1 (HGNC:55284): (ARHGEF18 antisense RNA 1)

ACMG classification

Our verdict: Likely_benign. The variant received -5 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0091762245).
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.000473 (72/152322) while in subpopulation AFR AF = 0.00118 (49/41576). AF 95% confidence interval is 0.000915. There are 0 homozygotes in GnomAd4. There are 28 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001367823.1. 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
	ARHGEF18	NM_001367823.1	MANE Select	c.34C>T	p.Arg12Trp	missense	Exon 3 of 29	NP_001354752.1	Q6ZSZ5-4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ARHGEF18	ENST00000668164.2	MANE Select	c.34C>T	p.Arg12Trp	missense	Exon 3 of 29	ENSP00000499655.2	Q6ZSZ5-4
	ARHGEF18	ENST00000671891.2		c.229C>T	p.Arg77Trp	missense	Exon 3 of 10	ENSP00000500339.2	A0A5F9ZHI8
	ARHGEF18-AS1	ENST00000795305.1		n.205+17746G>A		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.000466 AC: 71 AN: 152204 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00116

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000309

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000304 AC: 2 AN: 6572 AF XY: 0.00

Gnomad AFR exome AF: 0.00275

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad NFE exome AF: 0.000180

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000451 AC: 488 AN: 1082136 Hom.: 1 Cov.: 31 AF XY: 0.000415 AC XY: 212 AN XY: 510946

African (AFR) AF: 0.00122 AC: 28 AN: 23040

American (AMR) AF: 0.00 AC: 0 AN: 8426

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 14400

East Asian (EAS) AF: 0.00 AC: 0 AN: 26524

South Asian (SAS) AF: 0.00 AC: 0 AN: 19588

European-Finnish (FIN) AF: 0.000511 AC: 11 AN: 21530

Middle Eastern (MID) AF: 0.00132 AC: 6 AN: 4544

European-Non Finnish (NFE) AF: 0.000455 AC: 419 AN: 920220

Other (OTH) AF: 0.000547 AC: 24 AN: 43864

GnomAD4 genome AF: 0.000473 AC: 72 AN: 152322 Hom.: 0 Cov.: 32 AF XY: 0.000376 AC XY: 28 AN XY: 74482

African (AFR) AF: 0.00118 AC: 49 AN: 41576

American (AMR) AF: 0.0000654 AC: 1 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5178

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10622

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.000309 AC: 21 AN: 68032

Other (OTH) AF: 0.00 AC: 0 AN: 2116

Alfa AF: 0.000366 Hom.: 0

Bravo AF: 0.000567

TwinsUK AF: 0.000809 AC: 3

ALSPAC AF: 0.00130 AC: 5

ExAC AF: 0.000814 AC: 6

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 provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.087
BayesDel_addAF	Benign	-0.63	T
BayesDel_noAF	Benign	-0.68
CADD	Benign	14
DANN	Uncertain	1.0
FATHMM_MKL	Benign	0.032	N
LIST_S2	Benign	0.51	T
M_CAP	Benign	0.025	T
MetaRNN	Benign	0.0092	T
PhyloP100		0.44
Sift4G	Benign	0.086	T
Vest4		0.097
MVP		0.39
GERP RS		1.9
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.12		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: rs140250213; hg19: chr19-7437716;