chr19-7375737-C-CA

Variant names:

• chr19-7375737-C-CA
• rs1433105422
• NM_001367823.1:c.294dupA

Variant summary

Our verdict is Likely pathogenic. The variant received 9 ACMG points: 10P and 1B. PVS1 PP5_Moderate BS1_Supporting

The NM_001367823.1(ARHGEF18):​c.294dupA​(p.Ala99SerfsTer4) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000972 in 1,234,456 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: 𝑓 0.000026 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000074 (0 hom.)
• Consequence: ARHGEF18 NM_001367823.1 frameshift
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: -5.06
• 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_pathogenic. The variant received 9 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PP5: Variant 19-7375737-C-CA is Pathogenic according to our data. Variant chr19-7375737-C-CA is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 3892982.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.0000263 (4/152300) while in subpopulation EAS AF = 0.000773 (4/5172). AF 95% confidence interval is 0.000263. There are 0 homozygotes in GnomAd4. There are 2 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.294dupA	p.Ala99SerfsTer4	frameshift	Exon 4 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.294dupA	p.Ala99SerfsTer4	frameshift	Exon 4 of 29	ENSP00000499655.2	Q6ZSZ5-4
	ARHGEF18	ENST00000671891.2		c.489dupA	p.Ala164SerfsTer4	frameshift	Exon 4 of 10	ENSP00000500339.2	A0A5F9ZHI8
	ARHGEF18-AS1	ENST00000795305.1		n.205+14838dupT		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.0000263 AC: 4 AN: 152182 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000772

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000739 AC: 8 AN: 1082156 Hom.: 0 Cov.: 30 AF XY: 0.00000979 AC XY: 5 AN XY: 510960

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

American (AMR) AF: 0.00 AC: 0 AN: 8428

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

East Asian (EAS) AF: 0.000302 AC: 8 AN: 26534

South Asian (SAS) AF: 0.00 AC: 0 AN: 19582

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 21530

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4544

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 920224

Other (OTH) AF: 0.00 AC: 0 AN: 43872

GnomAD4 genome AF: 0.0000263 AC: 4 AN: 152300 Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2 AN XY: 74462

African (AFR) AF: 0.00 AC: 0 AN: 41576

American (AMR) AF: 0.00 AC: 0 AN: 15292

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

East Asian (EAS) AF: 0.000773 AC: 4 AN: 5172

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10614

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

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68024

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

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000227

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
PhyloP100		-5.1
Mutation Taster		=126/74	disease causing (fs/PTC)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: rs1433105422; hg19: chr19-7440623;