chr19-7439953-G-A

Variant names:

• chr19-7439953-G-A
• rs1974518447
• NM_001367823.1:c.968-391G>A

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001130955.2(ARHGEF18):​c.-150G>A variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000365 in 1,371,110 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000036 (0 hom.)
• Consequence: ARHGEF18 NM_001130955.2 5_prime_UTR
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.67
• 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 Gene-Disease associations (from GenCC):

• retinitis pigmentosa 78

  Inheritance: AR Classification: STRONG, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), G2P
• inherited retinal dystrophy

  Inheritance: AR Classification: MODERATE Submitted by: ClinGen
• retinitis pigmentosa

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.16256067).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001130955.2. 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.968-391G>A		intron	N/A	NP_001354752.1	Q6ZSZ5-4
	ARHGEF18	NM_001130955.2		c.-150G>A		5_prime_UTR	Exon 1 of 20	NP_001124427.2	A0A3B3IPE9
	ARHGEF18	NM_001367824.1		c.-226-236G>A		intron	N/A	NP_001354753.1	Q6ZSZ5-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ARHGEF18	ENST00000668164.2	MANE Select	c.968-391G>A		intron	N/A	ENSP00000499655.2	Q6ZSZ5-4
	ARHGEF18	ENST00000617428.4	TSL:1	c.-226-236G>A		intron	N/A	ENSP00000482647.4	Q6ZSZ5-2
	ARHGEF18	ENST00000319670.14	TSL:1	c.-71-391G>A		intron	N/A	ENSP00000319200.8	A0A804CAZ4

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 0.00000365 AC: 5 AN: 1371110 Hom.: 0 Cov.: 39 AF XY: 0.00000148 AC XY: 1 AN XY: 673514

African (AFR) AF: 0.00 AC: 0 AN: 29994

American (AMR) AF: 0.00 AC: 0 AN: 30070

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 23868

East Asian (EAS) AF: 0.00 AC: 0 AN: 35246

South Asian (SAS) AF: 0.00 AC: 0 AN: 77894

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 48510

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5088

European-Non Finnish (NFE) AF: 0.00000470 AC: 5 AN: 1063978

Other (OTH) AF: 0.00 AC: 0 AN: 56462

GnomAD4 genome Cov.: 31

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

ClinVar submissions as Germline

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	Pathogenic	0.63
BayesDel_addAF	Benign	-0.12	T
BayesDel_noAF	Benign	-0.40
CADD	Benign	22
DANN	Uncertain	1.0
Eigen	Benign	-0.22
Eigen_PC	Benign	-0.081
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Benign	0.53	T
M_CAP	Benign	0.014	T
MetaRNN	Benign	0.16	T
MetaSVM	Benign	-1.1	T
PhyloP100		2.7
PrimateAI	Uncertain	0.65	T
PROVEAN	Benign	-0.68	N
REVEL	Benign	0.027
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Vest4		0.22
MutPred		0.33		Gain of MoRF binding (P = 5e-04)
MVP		0.45
MPC		1.1
ClinPred		0.56	D
GERP RS		3.0
PromoterAI		0.032	Neutral
gMVP		0.059

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs1974518447; hg19: chr19-7504839;