chr9-36249334-G-A
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Variant summary
Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PVS1PP5_Very_Strong
The NM_005476.7(GNE):c.22C>T(p.Arg8*) variant causes a stop gained change. The variant allele was found at a frequency of 0.0000239 in 1,461,606 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: not found (cov: 32)
Exomes 𝑓: 0.000024 ( 0 hom. )
Consequence
GNE
NM_005476.7 stop_gained
NM_005476.7 stop_gained
Scores
4
2
1
Clinical Significance
Conservation
PhyloP100: 3.65
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 16 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 149 pathogenic variants in the truncated region.
PP5
Variant 9-36249334-G-A is Pathogenic according to our data. Variant chr9-36249334-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 552994.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-36249334-G-A is described in Lovd as [Pathogenic].
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD3 genomes
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32
GnomAD3 exomes AF: 0.00000796 AC: 2AN: 251278Hom.: 0 AF XY: 0.0000147 AC XY: 2AN XY: 135822
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GnomAD4 exome AF: 0.0000239 AC: 35AN: 1461606Hom.: 0 Cov.: 31 AF XY: 0.0000193 AC XY: 14AN XY: 727102
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GnomAD4 genome Cov.: 32
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ClinVar
Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:4
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
GNE myopathy Pathogenic:3
Likely pathogenic, criteria provided, single submitter | clinical testing | Institute for Medical Genetics and Human Genetics, Charité - Universitätsmedizin Berlin | Sep 16, 2022 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Counsyl | Jul 24, 2017 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Mar 07, 2024 | - - |
Sialuria;C1853926:GNE myopathy Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Oct 18, 2023 | This sequence change creates a premature translational stop signal (p.Arg39*) 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). This variant is present in population databases (rs766420673, gnomAD 0.002%). This premature translational stop signal has been observed in individual(s) with autosomal recessive GNE-related myopathy (PMID: 20059379, 22507750). This variant is also known as p.Arg8*. ClinVar contains an entry for this variant (Variation ID: 552994). For these reasons, this variant has been classified as Pathogenic. - |
Computational scores
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Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Uncertain
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Uncertain
D
Vest4
0.92, 0.84, 0.83
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
Find out detailed SpliceAI scores and Pangolin per-transcript scores at