rs786204735
Variant summary
Our verdict is Pathogenic. Variant got 13 ACMG points: 13P and 0B. PP2PP3_StrongPP5_Very_Strong
The ENST00000396594.8(GNE):c.479G>A(p.Arg160Gln) variant causes a missense change. The variant allele was found at a frequency of 0.00000889 in 1,461,762 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 (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R160G) has been classified as Uncertain significance.
Frequency
Consequence
ENST00000396594.8 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 13 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
GNE | NM_001128227.3 | c.479G>A | p.Arg160Gln | missense_variant | 3/12 | ENST00000396594.8 | NP_001121699.1 | |
GNE | NM_005476.7 | c.386G>A | p.Arg129Gln | missense_variant | 3/12 | ENST00000642385.2 | NP_005467.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
GNE | ENST00000396594.8 | c.479G>A | p.Arg160Gln | missense_variant | 3/12 | 1 | NM_001128227.3 | ENSP00000379839 | ||
GNE | ENST00000642385.2 | c.386G>A | p.Arg129Gln | missense_variant | 3/12 | NM_005476.7 | ENSP00000494141 | P1 |
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD3 exomes AF: 0.00000398 AC: 1AN: 251360Hom.: 0 AF XY: 0.00000736 AC XY: 1AN XY: 135860
GnomAD4 exome AF: 0.00000889 AC: 13AN: 1461762Hom.: 0 Cov.: 33 AF XY: 0.0000138 AC XY: 10AN XY: 727194
GnomAD4 genome Cov.: 32
ClinVar
Submissions by phenotype
GNE myopathy Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | May 30, 2024 | Variant summary: GNE c.479G>A (p.Arg160Gln) results in a conservative amino acid change located in the UDP-N-acetylglucosamine 2-epimerase domain (IPR003331) of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4e-06 in 251360 control chromosomes. c.479G>A has been reported in the literature in compound heterozygous individuals affected with Inclusion Body Myopathy 2 (Chaouch_2014, Granger_2022, Mori-Yoshimura_2012, Tomimitsu_2004, Guo_2022). 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. The most pronounced variant effect results in hyposialylation in human pluripotent stem cells (hPSCs) (Park_2022). The following publications have been ascertained in the context of this evaluation (PMID: 24695763, 35933247, 35438352, 16372135, 22507750, 35202935, 15136692). ClinVar contains an entry for this variant (Variation ID: 189156). Based on the evidence outlined above, the variant was classified as pathogenic. - |
Likely pathogenic, criteria provided, single submitter | literature only | Counsyl | Jan 26, 2015 | - - |
Sialuria;C1853926:GNE myopathy Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Mar 17, 2023 | 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. For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 189156). This variant is also known as p.Arg129Gln. This missense change has been observed in individual(s) with GNE myopathy/distal myopathy with rimmed vacuoles (PMID: 15136692, 16372135, 22507750, 23127962, 24695763). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is present in population databases (rs748704459, gnomAD 0.0009%). This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 160 of the GNE protein (p.Arg160Gln). - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at