chr9-36227397-C-A
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Variant summary
Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM5PP2PP5
The NM_005476.7(GNE):c.1132G>T(p.Asp378Tyr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000375 in 1,612,536 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D378H) has been classified as Pathogenic.
Frequency
Genomes: 𝑓 0.00020 ( 0 hom., cov: 31)
Exomes 𝑓: 0.00039 ( 0 hom. )
Consequence
GNE
NM_005476.7 missense
NM_005476.7 missense
Scores
6
10
3
Clinical Significance
Conservation
PhyloP100: 2.90
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 Uncertain_significance. Variant got 4 ACMG points.
PM5
Other missense variant is known to change same aminoacid residue: Variant chr9-36227397-C-G is described in Lovd as [Pathogenic].
PP2
Missense variant in gene, where missense usually causes diseases (based on misZ statistic), GNE. . Gene score misZ 2.5904 (greater than the threshold 3.09). Trascript score misZ 3.9915 (greater than threshold 3.09). GenCC has associacion of gene with macrothrombocytopenia, isolated, platelet-type bleeding disorder 19, sialuria, GNE myopathy.
PP5
Variant 9-36227397-C-A is Pathogenic according to our data. Variant chr9-36227397-C-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 283278.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=1, not_provided=2, Pathogenic=9}. Variant chr9-36227397-C-A is described in Lovd as [Pathogenic].
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|
| GNE | NM_001128227.3 | c.1225G>T | p.Asp409Tyr | missense_variant | 7/12 | ENST00000396594.8 | NP_001121699.1 | |
| GNE | NM_005476.7 | c.1132G>T | p.Asp378Tyr | missense_variant | 7/12 | ENST00000642385.2 | NP_005467.1 |
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|---|
| GNE | ENST00000396594.8 | c.1225G>T | p.Asp409Tyr | missense_variant | 7/12 | 1 | NM_001128227.3 | ENSP00000379839.3 | ||
| GNE | ENST00000642385.2 | c.1132G>T | p.Asp378Tyr | missense_variant | 7/12 | NM_005476.7 | ENSP00000494141.2 |
Frequencies
GnomAD3 genomes 0.000204 AC: 31AN: 152106Hom.: 0 Cov.: 31
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GnomAD3 exomes AF: 0.000159 AC: 40AN: 251400Hom.: 0 AF XY: 0.000184 AC XY: 25AN XY: 135888
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GnomAD4 exome AF: 0.000393 AC: 574AN: 1460430Hom.: 0 Cov.: 30 AF XY: 0.000356 AC XY: 259AN XY: 726622
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GnomAD4 genome 0.000204 AC: 31AN: 152106Hom.: 0 Cov.: 31 AF XY: 0.000148 AC XY: 11AN XY: 74302
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Pathogenic:10Uncertain:1Other:2
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
GNE myopathy Pathogenic:5Other:1
| Pathogenic, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Aug 25, 2016 | The p.Asp409Tyr variant in GNE has been reported in at least 12 compound heteroz ygous patients from 9 families (Chaouch 2014). In addition, this variant has bee n identified in 0.01% (14/121,022) of chromosomes by the Exome Aggregation Conso rtium (ExAC, http://exac.broadinstitute.org; dbSNP rs199877522). Although this v ariant has been seen in the general population, its frequency is low enough to b e consistent with a carrier frequency. In vitro functional studies support an im pact to protein function (Noguchi 2004, Penner 2006). In summary, this variant m eets criteria to be classified as pathogenic for GNE-related myopathy based on g enetic and functional data. - |
| Pathogenic, no assertion criteria provided | clinical testing | Natera, Inc. | Sep 16, 2020 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Myriad Genetics, Inc. | Dec 26, 2019 | NM_001128227.2(GNE):c.1225G>T(D409Y) is classified as pathogenic in the context of GNE myopathy. Sources cited for classification include the following: PMID 12473753, 24695763, 14707127 and 16503651. Classification of NM_001128227.2(GNE):c.1225G>T(D409Y) is based on the following criteria: This is a well-established pathogenic variant in the literature that has been observed more frequently in patients with clinical diagnoses than in healthy populations. Please note: this variant was assessed in the context of healthy population screening. - |
| not provided, no classification provided | literature only | GeneReviews | - | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Feb 05, 2024 | Variant summary: GNE c.1225G>T (p.Asp409Tyr) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00016 in 251400 control chromosomes (gnomAD). This frequency is not significantly higher than estimated for a pathogenic variant in GNE causing Inclusion Body Myopathy 2 (0.00016 vs 0.0011), allowing no conclusion about variant significance. c.1225G>T has been reported in the literature in multiple individuals affected with Inclusion Body Myopathy 2 (Noguchi_2004, Pogoryelova_2019). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function and this variant results in reduced enzyme activity (Noguchi_2004). The following publications have been ascertained in the context of this evaluation (PMID: 14707127, 30842975). ClinVar contains an entry for this variant (Variation ID: 283278). Based on the evidence outlined above, the variant was classified as pathogenic. - |
| Pathogenic, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Oct 09, 2018 | Variants in the GNE gene are known to cause GNE-related myopathies. The GNE c.1132G>T (p.Asp378Tyr) missense variant has been reported in at least three studies in which it is found in a compound heterozygous state in a total of five individuals with GNE-related myopathy (two of whom were related) (Eisenberg et al. 2003; Nishino et al. 2002; Leoyklang et al. 2014). The p.Asp378Tyr variant was absent from 50 control subjects and is reported at a frequency of 0.000324 in the European (non-Finnish) population of the Genome Aggregation Database. In vitro studies showed that p.Asp378Tyr variant was associated with 60% reduction of epimerase and a 50% reduction of kinase activity compared to wild type (Penner et al., 2006). Based on the evidence, the p.Asp378Tyr variant is classified as pathogenic for GNE-related myopathies. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. - |
not provided Pathogenic:3
| Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Mar 01, 2022 | Published functional studies demonstrate a damaging effect (60% reduction in epimerase activity and 50% reduction in kinase activity as compared to wild type) (Penner et al., 2006); Missense variants in this gene are often considered pathogenic (HGMD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 29305133, 12497639, 24695763, 16503651, 14707127, 12473753, 29382405, 19917666, 30467490, 30609409, 31127727, 24796702, 19596068, 27829678, 25123033, 24027297, 20301439, 29997562, 28641925, 30564623, 12325084, 26968811) - |
| Pathogenic, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Sep 11, 2015 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Apr 05, 2022 | - - |
Sialuria;C1853926:GNE myopathy Pathogenic:1Other:1
| Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jan 29, 2024 | This sequence change replaces aspartic acid, which is acidic and polar, with tyrosine, which is neutral and polar, at codon 409 of the GNE protein (p.Asp409Tyr). This variant is present in population databases (rs199877522, gnomAD 0.03%). This missense change has been observed in individuals with autosomal recessive GNE-related myopathy (PMID: 12473753, 12497639, 24695763). It is commonly reported in individuals of European ancestry (PMID: 12473753, 12497639, 24695763). This variant is also known as p.D378Y. ClinVar contains an entry for this variant (Variation ID: 283278). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on GNE protein function. Experimental studies have shown that this missense change affects GNE function (PMID: 14707127, 16503651). For these reasons, this variant has been classified as Pathogenic. - |
| not provided, no classification provided | phenotyping only | GenomeConnect - Invitae Patient Insights Network | - | Variant interpreted as Pathogenic and reported on 07-27-2020 by Invitae. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. Phenotypic details are available under supporting information. - |
Inborn genetic diseases Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Nov 17, 2023 | The c.1225G>T (p.D409Y) alteration is located in coding exon 7 of the GNE gene. This alteration results from a G to T substitution at nucleotide position 1225, causing the aspartic acid (D) at amino acid position 409 to be replaced by a tyrosine (Y)._x000D_ _x000D_ Based on the available evidence, the GNE c.1225G>T (p.D409Y) alteration is classified as pathogenic for autosomal recessive Nonaka myopathy; however, its clinical significance for autosomal dominant sialuria is uncertain. Based on data from gnomAD, the T allele has an overall frequency of 0.016% (45/282778) total alleles studied. The highest observed frequency was 0.033% (42/129128) of European (non-Finnish) alleles. This variant has been described as a British founder mutation after being reported in compound heterozygous form in numerous individuals affected with clinical and pathological findings consistent with GNE-related myopathy (Chaouch, 2014; Carrillo, 2018; Soule, 2018). This amino acid position is well conserved in available vertebrate species. This alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this alteration is classified as pathogenic. - |
Sialuria Uncertain:1
| Uncertain significance, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Apr 27, 2017 | This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. - |
Computational scores
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Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Uncertain
DEOGEN2
Pathogenic
D;.;D;.;.;.;D
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Uncertain
D
LIST_S2
Uncertain
.;D;D;D;D;D;.
M_CAP
Pathogenic
D
MetaRNN
Uncertain
D;D;D;D;D;D;D
MetaSVM
Pathogenic
D
MutationAssessor
Benign
L;.;L;.;.;L;L
PrimateAI
Uncertain
T
PROVEAN
Uncertain
.;D;D;N;D;D;D
REVEL
Pathogenic
Sift
Uncertain
.;D;D;D;D;D;D
Sift4G
Uncertain
.;D;D;D;D;D;D
Polyphen
D;D;D;.;.;.;D
Vest4
0.87, 0.88, 0.83, 0.79, 0.75, 0.87
MVP
0.99
MPC
1.6
ClinPred
T
GERP RS
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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