19-7373072-G-T

Variant names:

• chr19-7373072-G-T
• rs1970274686
• NM_001367823.1:c.275+1G>T

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PVS1 PP5_Moderate

The NM_001367823.1(ARHGEF18):​c.275+1G>T variant causes a splice donor, intron change. The variant allele was found at a frequency of 0.00000462 in 1,082,186 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 1/1 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000046 (0 hom.)
• Consequence: ARHGEF18 NM_001367823.1 splice_donor, intron
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 4.71
• 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: Splicing +-2 bp (donor or acceptor) variant, LoF is a know mechanism of disease, No cryptic splice site detected. Exon removal results in frameshift change.
• PP5: Variant 19-7373072-G-T is Pathogenic according to our data. Variant chr19-7373072-G-T is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 3393420.Status of the report is criteria_provided_single_submitter, 1 stars.

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.275+1G>T		splice_donor intron	N/A	NP_001354752.1	Q6ZSZ5-4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ARHGEF18	ENST00000668164.2	MANE Select	c.275+1G>T		splice_donor intron	N/A	ENSP00000499655.2	Q6ZSZ5-4
	ARHGEF18	ENST00000671891.2		c.470+1G>T		splice_donor intron	N/A	ENSP00000500339.2	A0A5F9ZHI8
	ARHGEF18-AS1	ENST00000795305.1		n.205+17504C>A		intron	N/A

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000462 AC: 5 AN: 1082186 Hom.: 0 Cov.: 31 AF XY: 0.00000587 AC XY: 3 AN XY: 510992

African (AFR) AF: 0.00 AC: 0 AN: 23042

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

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 14398

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

South Asian (SAS) AF: 0.000255 AC: 5 AN: 19582

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 21524

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4530

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 920294

Other (OTH) AF: 0.00 AC: 0 AN: 43864

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions

Significance: Likely pathogenic

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
1	-	-	Retinitis pigmentosa 78 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.18	D
BayesDel_noAF	Uncertain	0.020
CADD	Pathogenic	26
DANN	Uncertain	0.99
FATHMM_MKL	Uncertain	0.86	D
PhyloP100		4.7
GERP RS		4.0
Mutation Taster		=82/18	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.98		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.98		Position offset: -1

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs1970274686; hg19: chr19-7437958;