rs1057516374
Positions:
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_001128227.3(GNE):c.1009C>T(p.Arg337Ter) variant causes a stop gained change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Variant results in nonsense mediated mRNA decay.
Frequency
Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)
Failed GnomAD Quality Control
Consequence
GNE
NM_001128227.3 stop_gained
NM_001128227.3 stop_gained
Scores
3
3
1
Clinical Significance
Conservation
PhyloP100: 5.82
Genes affected
GNE (HGNC:23657): (glucosamine (UDP-N-acetyl)-2-epimerase/N-acetylmannosamine kinase) The protein encoded by this gene is a bifunctional enzyme that initiates and regulates the biosynthesis of N-acetylneuraminic acid (NeuAc), a precursor of sialic acids. It is a rate-limiting enzyme in the sialic acid biosynthetic pathway. Sialic acid modification of cell surface molecules is crucial for their function in many biologic processes, including cell adhesion and signal transduction. Differential sialylation of cell surface molecules is also implicated in the tumorigenicity and metastatic behavior of malignant cells. Mutations in this gene are associated with sialuria, autosomal recessive inclusion body myopathy, and Nonaka myopathy. Alternative splicing of this gene results in transcript variants encoding different isoforms. [provided by RefSeq, Jul 2008]
CLTA (HGNC:2090): (clathrin light chain A) Clathrin is a large, soluble protein composed of heavy and light chains. It functions as the main structural component of the lattice-type cytoplasmic face of coated pits and vesicles which entrap specific macromolecules during receptor-mediated endocytosis. This gene encodes one of two clathrin light chain proteins which are believed to function as regulatory elements. Alternative splicing results in multiple transcript variants. Related pseudogenes have been identified on chromosomes 8 and 12. [provided by RefSeq, May 2010]
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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 9-36233986-G-A is Pathogenic according to our data. Variant chr9-36233986-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 370285.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
GNE | NM_001128227.3 | c.1009C>T | p.Arg337Ter | stop_gained | 5/12 | ENST00000396594.8 | |
GNE | NM_005476.7 | c.916C>T | p.Arg306Ter | stop_gained | 5/12 | ENST00000642385.2 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
GNE | ENST00000396594.8 | c.1009C>T | p.Arg337Ter | stop_gained | 5/12 | 1 | NM_001128227.3 | ||
GNE | ENST00000642385.2 | c.916C>T | p.Arg306Ter | stop_gained | 5/12 | NM_005476.7 | P1 |
Frequencies
GnomAD3 genomes AF: 0.00 AC: 1AN: 152090Hom.: 0 Cov.: 32 FAILED QC
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GnomAD4 exome Cov.: 31
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GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.00000658 AC: 1AN: 152090Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1AN XY: 74284
GnomAD4 genome
Data not reliable, filtered out with message: AS_VQSR
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ClinVar
Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:6
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
GNE myopathy Pathogenic:3
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Dec 22, 2023 | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Counsyl | Jan 04, 2016 | - - |
Pathogenic, no assertion criteria provided | clinical testing | Natera, Inc. | Jun 03, 2021 | - - |
Sialuria;C1853926:GNE myopathy Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Oct 20, 2023 | This sequence change creates a premature translational stop signal (p.Arg337*) in the GNE gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in GNE are known to be pathogenic (PMID: 24027297). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This premature translational stop signal has been observed in individuals with autosomal recessive GNE myopathy (PMID: 25986339, 29480215). This variant is also known as p.Arg306*. ClinVar contains an entry for this variant (Variation ID: 370285). For these reasons, this variant has been classified as Pathogenic. - |
Pathogenic, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Dec 03, 2021 | - - |
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Oct 28, 2020 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Uncertain
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Pathogenic
D
MutationTaster
Benign
A;A;A;A;A;A
Vest4
0.98, 0.98, 0.93, 0.92, 0.97
GERP RS
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