rs987233144
Variant summary
Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM2PP3_StrongPP5_Moderate
The NM_001367823.1(ARHGEF18):c.1372A>G(p.Thr458Ala) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000018 in 1,613,130 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 Likely pathogenic (★).
Frequency
Genomes: 𝑓 0.000020 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000018 ( 0 hom. )
Consequence
ARHGEF18
NM_001367823.1 missense
NM_001367823.1 missense
Scores
11
4
1
Clinical Significance
Conservation
PhyloP100: 9.32
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]
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ACMG classification
Classification made for transcript
Verdict is Likely_pathogenic. Variant got 8 ACMG points.
PM2
?
Very rare variant in population databases, with high coverage;
PP3
?
MetaRNN computational evidence supports a deleterious effect, 0.985
PP5
?
Variant 19-7444215-A-G is Pathogenic according to our data. Variant chr19-7444215-A-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 417754.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr19-7444215-A-G is described in Lovd as [Pathogenic]. Variant chr19-7444215-A-G is described in Lovd as [Likely_pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
ARHGEF18 | NM_001367823.1 | c.1372A>G | p.Thr458Ala | missense_variant | 14/29 | ENST00000668164.2 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
ARHGEF18 | ENST00000668164.2 | c.1372A>G | p.Thr458Ala | missense_variant | 14/29 | NM_001367823.1 | A2 |
Frequencies
GnomAD3 genomes ? AF: 0.0000197 AC: 3AN: 152226Hom.: 0 Cov.: 32
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GnomAD4 exome AF: 0.0000178 AC: 26AN: 1460904Hom.: 0 Cov.: 31 AF XY: 0.0000220 AC XY: 16AN XY: 726704
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GnomAD4 genome ? AF: 0.0000197 AC: 3AN: 152226Hom.: 0 Cov.: 32 AF XY: 0.0000134 AC XY: 1AN XY: 74364
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ClinVar
Significance: Likely pathogenic
Submissions summary: Pathogenic:2
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
Retinitis pigmentosa 78 Pathogenic:1
Pathogenic, no assertion criteria provided | literature only | OMIM | Apr 07, 2017 | - - |
not provided Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Invitae | Sep 15, 2023 | In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. Experimental studies have shown that this missense change affects ARHGEF18 function (PMID: 28132693). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. ClinVar contains an entry for this variant (Variation ID: 417754). This missense change has been observed in individual(s) with inherited retinal dystrophy (PMID: 28132693; Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is present in population databases (no rsID available, gnomAD 0.007%). This sequence change replaces threonine, which is neutral and polar, with alanine, which is neutral and non-polar, at codon 270 of the ARHGEF18 protein (p.Thr270Ala). - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
Cadd
Pathogenic
Dann
Uncertain
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Pathogenic
D
LIST_S2
Pathogenic
D;D
M_CAP
Uncertain
D
MetaRNN
Pathogenic
D;D
MetaSVM
Uncertain
D
MutationTaster
Benign
D;D
PrimateAI
Uncertain
T
PROVEAN
Pathogenic
D;D
REVEL
Pathogenic
Sift
Pathogenic
D;D
Sift4G
Pathogenic
D;D
Vest4
MutPred
0.87
.;Loss of catalytic residue at T270 (P = 0.0331);
MVP
MPC
1.0
ClinPred
D
GERP RS
gMVP
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at