rs587777293
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Variant summary
Our verdict is Pathogenic. Variant got 19 ACMG points: 19P and 0B. PVS1PM2PP3PP5_Very_Strong
The NM_152305.3(POGLUT1):c.11G>A(p.Trp4Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000124 in 1,608,512 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 0.0000066 ( 0 hom., cov: 33)
Exomes 𝑓: 6.9e-7 ( 0 hom. )
Consequence
POGLUT1
NM_152305.3 stop_gained
NM_152305.3 stop_gained
Scores
1
6
Clinical Significance
Conservation
PhyloP100: -0.560
Genes affected
POGLUT1 (HGNC:22954): (protein O-glucosyltransferase 1) This gene encodes a protein with both O-glucosyltransferase and O-xylosyltransferase activity which localizes to the lumen of the endoplasmic reticulum. This protein has a carboxy-terminal KTEL motif which is predicted to function as an endoplasmic reticulum retention signal. This gene is an essential regulator of Notch signalling and likely plays a role in cell fate and tissue formation during development. It may also play a role in the pathogenesis of leukemia. Mutations in this gene have been associated with the autosomal dominant genodermatosis Dowling-Degos disease 4. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Apr 2014]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 19 ACMG points.
PVS1
?
Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant located near the start codon (<100nt), not predicted to undergo nonsense mediated mRNA decay. There are 47 pathogenic variants in the truncated region.
PM2
?
Very rare variant in population databases, with high coverage;
PP3
?
Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
PP5
?
Variant 3-119469032-G-A is Pathogenic according to our data. Variant chr3-119469032-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 126528.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-119469032-G-A is described in Lovd as [Likely_pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
POGLUT1 | NM_152305.3 | c.11G>A | p.Trp4Ter | stop_gained | 1/11 | ENST00000295588.9 | |
POGLUT1 | NR_024265.2 | n.70G>A | non_coding_transcript_exon_variant | 1/11 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
POGLUT1 | ENST00000295588.9 | c.11G>A | p.Trp4Ter | stop_gained | 1/11 | 1 | NM_152305.3 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.00000657 AC: 1AN: 152244Hom.: 0 Cov.: 33
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GnomAD3 exomes AF: 0.00000425 AC: 1AN: 235280Hom.: 0 AF XY: 0.00000777 AC XY: 1AN XY: 128652
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GnomAD4 exome AF: 6.87e-7 AC: 1AN: 1456268Hom.: 0 Cov.: 30 AF XY: 0.00000138 AC XY: 1AN XY: 724402
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GnomAD4 genome ? AF: 0.00000657 AC: 1AN: 152244Hom.: 0 Cov.: 33 AF XY: 0.0000134 AC XY: 1AN XY: 74368
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ClinVar
Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:3
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not provided Pathogenic:2
Likely pathogenic, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Sep 20, 2022 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jun 30, 2022 | For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. ClinVar contains an entry for this variant (Variation ID: 126528). This premature translational stop signal has been observed in individual(s) with Dowling-Degos disease (PMID: 24387993). This variant is present in population databases (rs587777293, gnomAD 0.001%). This sequence change creates a premature translational stop signal (p.Trp4*) in the POGLUT1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in POGLUT1 are known to be pathogenic (PMID: 24387993). - |
Dowling-Degos disease 4 Pathogenic:1
Pathogenic, no assertion criteria provided | literature only | OMIM | Jan 02, 2014 | - - |
Computational scores
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Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Benign
CADD
Pathogenic
DANN
Benign
Eigen
Benign
Eigen_PC
Benign
FATHMM_MKL
Benign
N
MutationTaster
Benign
A
Vest4
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
DS_DG_spliceai
Position offset: -3
Find out detailed SpliceAI scores and Pangolin per-transcript scores at