NM_001367823.1:c.625G>T

Variant names:

• chr19-7379147-G-T
• rs1970605801
• NM_001367823.1:c.625G>T

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PVS1 PM2

The NM_001367823.1(ARHGEF18):​c.625G>T​(p.Glu209*) variant causes a stop gained change. The variant allele was found at a frequency of 0.000000926 in 1,080,342 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 9.3e-7 (0 hom.)
• Consequence: ARHGEF18 NM_001367823.1 stop_gained
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.22
• 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: Pathogenic. The variant received 10 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage

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.625G>T	p.Glu209*	stop_gained	Exon 7 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.625G>T	p.Glu209*	stop_gained	Exon 7 of 29	ENSP00000499655.2	Q6ZSZ5-4
	ARHGEF18	ENST00000671891.2		c.820G>T	p.Glu274*	stop_gained	Exon 7 of 10	ENSP00000500339.2	A0A5F9ZHI8
	ARHGEF18-AS1	ENST00000795305.1		n.205+11429C>A		intron	N/A

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 9.26e-7 AC: 1 AN: 1080342 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 510190

African (AFR) AF: 0.00 AC: 0 AN: 22982

American (AMR) AF: 0.00 AC: 0 AN: 8424

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 14386

East Asian (EAS) AF: 0.00 AC: 0 AN: 26526

South Asian (SAS) AF: 0.00 AC: 0 AN: 19496

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 21552

Middle Eastern (MID) AF: 0.000343 AC: 1 AN: 2918

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 920370

Other (OTH) AF: 0.00 AC: 0 AN: 43688

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

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
BayesDel_addAF	Pathogenic	0.55	D
BayesDel_noAF	Pathogenic	0.56
CADD	Pathogenic	45
DANN	Uncertain	1.0
FATHMM_MKL	Uncertain	0.91	D
PhyloP100		5.2
Vest4		0.37
GERP RS		4.0
Mutation Taster		=131/69	disease causing (fs/PTC)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.080		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: rs1970605801; hg19: chr19-7444033;