rs138924661
Positions:
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_003647.3(DGKE):c.966G>A(p.Trp322Ter) variant causes a stop gained change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000183 in 1,614,056 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 Pathogenic (★★). Variant results in nonsense mediated mRNA decay.
Frequency
Genomes: 𝑓 0.00015 ( 0 hom., cov: 32)
Exomes 𝑓: 0.00019 ( 0 hom. )
Consequence
DGKE
NM_003647.3 stop_gained
NM_003647.3 stop_gained
Scores
5
1
1
Clinical Significance
Conservation
PhyloP100: 9.15
Genes affected
DGKE (HGNC:2852): (diacylglycerol kinase epsilon) Diacylglycerol kinases are thought to be involved mainly in the regeneration of phosphatidylinositol (PI) from diacylglycerol in the PI-cycle during cell signal transduction. When expressed in mammalian cells, DGK-epsilon shows specificity for arachidonyl-containing diacylglycerol. DGK-epsilon is expressed predominantly in testis. [provided by RefSeq, Jul 2008]
TRIM25 (HGNC:12932): (tripartite motif containing 25) The protein encoded by this gene is a member of the tripartite motif (TRIM) family. The TRIM motif includes three zinc-binding domains, a RING, a B-box type 1 and a B-box type 2, and a coiled-coil region. The protein is an RNA binding protein, functions as a ubiquitin E3 ligase and is involved in multiple cellular processes, including regulation of antiviral innate immunity. [provided by RefSeq, Sep 2021]
Genome browser will be placed here
ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 18 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;
PP5
Variant 17-56848773-G-A is Pathogenic according to our data. Variant chr17-56848773-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 135641.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-56848773-G-A is described in Lovd as [Pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
DGKE | NM_003647.3 | c.966G>A | p.Trp322Ter | stop_gained | 6/12 | ENST00000284061.8 | NP_003638.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
DGKE | ENST00000284061.8 | c.966G>A | p.Trp322Ter | stop_gained | 6/12 | 1 | NM_003647.3 | ENSP00000284061 | P1 | |
DGKE | ENST00000572944.1 | c.798G>A | p.Trp266Ter | stop_gained | 5/10 | 1 | ENSP00000458493 | |||
TRIM25 | ENST00000648772.1 | c.*313+3170C>T | intron_variant, NMD_transcript_variant | ENSP00000498158 |
Frequencies
GnomAD3 genomes AF: 0.000151 AC: 23AN: 152200Hom.: 0 Cov.: 32
GnomAD3 genomes
AF:
AC:
23
AN:
152200
Hom.:
Cov.:
32
Gnomad AFR
AF:
Gnomad AMI
AF:
Gnomad AMR
AF:
Gnomad ASJ
AF:
Gnomad EAS
AF:
Gnomad SAS
AF:
Gnomad FIN
AF:
Gnomad MID
AF:
Gnomad NFE
AF:
Gnomad OTH
AF:
GnomAD3 exomes AF: 0.0000915 AC: 23AN: 251454Hom.: 0 AF XY: 0.000103 AC XY: 14AN XY: 135894
GnomAD3 exomes
AF:
AC:
23
AN:
251454
Hom.:
AF XY:
AC XY:
14
AN XY:
135894
Gnomad AFR exome
AF:
Gnomad AMR exome
AF:
Gnomad ASJ exome
AF:
Gnomad EAS exome
AF:
Gnomad SAS exome
AF:
Gnomad FIN exome
AF:
Gnomad NFE exome
AF:
Gnomad OTH exome
AF:
GnomAD4 exome AF: 0.000187 AC: 273AN: 1461856Hom.: 0 Cov.: 31 AF XY: 0.000161 AC XY: 117AN XY: 727228
GnomAD4 exome
AF:
AC:
273
AN:
1461856
Hom.:
Cov.:
31
AF XY:
AC XY:
117
AN XY:
727228
Gnomad4 AFR exome
AF:
Gnomad4 AMR exome
AF:
Gnomad4 ASJ exome
AF:
Gnomad4 EAS exome
AF:
Gnomad4 SAS exome
AF:
Gnomad4 FIN exome
AF:
Gnomad4 NFE exome
AF:
Gnomad4 OTH exome
AF:
GnomAD4 genome AF: 0.000151 AC: 23AN: 152200Hom.: 0 Cov.: 32 AF XY: 0.0000807 AC XY: 6AN XY: 74354
GnomAD4 genome
AF:
AC:
23
AN:
152200
Hom.:
Cov.:
32
AF XY:
AC XY:
6
AN XY:
74354
Gnomad4 AFR
AF:
Gnomad4 AMR
AF:
Gnomad4 ASJ
AF:
Gnomad4 EAS
AF:
Gnomad4 SAS
AF:
Gnomad4 FIN
AF:
Gnomad4 NFE
AF:
Gnomad4 OTH
AF:
Alfa
AF:
Hom.:
Bravo
AF:
ESP6500AA
AF:
AC:
0
ESP6500EA
AF:
AC:
2
ExAC
AF:
AC:
7
EpiCase
AF:
EpiControl
AF:
ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:6Other:1
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Immunoglobulin-mediated membranoproliferative glomerulonephritis Pathogenic:3
Pathogenic, criteria provided, single submitter | clinical testing | Centre for Mendelian Genomics, University Medical Centre Ljubljana | Jun 12, 2019 | This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PVS1,PS1,PM2. - |
Pathogenic, criteria provided, single submitter | research | Center for Precision Medicine, Vanderbilt University Medical Center | Mar 16, 2018 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Apr 07, 2022 | - - |
Atypical hemolytic-uremic syndrome Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | Genome Diagnostics Laboratory, The Hospital for Sick Children | Apr 01, 2020 | - - |
Likely pathogenic, no assertion criteria provided | literature only | Richard Lifton Laboratory, Yale University School of Medicine | - | - - |
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Dec 07, 2023 | This sequence change creates a premature translational stop signal (p.Trp322*) in the DGKE gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in DGKE are known to be pathogenic (PMID: 23274426, 23542698). This variant is present in population databases (rs138924661, gnomAD 0.02%). This premature translational stop signal has been observed in individuals with nephrotic syndrome and atypical hemolytic uremic syndrome (PMID: 23542698, 25135762, 25854283, 28496993). ClinVar contains an entry for this variant (Variation ID: 135641). For these reasons, this variant has been classified as Pathogenic. - |
AHUS, SUSCEPTIBILITY TO, 7 Other:1
risk factor, no assertion criteria provided | literature only | OMIM | May 01, 2013 | - - |
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
MutationTaster
Benign
A
Vest4
GERP RS
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at