rs759945787
Variant summary
Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2PP2PP5
The NM_005476.7(GNE):c.722T>G(p.Ile241Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000186 in 1,613,530 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Consequence
NM_005476.7 missense
Scores
Clinical Significance
Conservation
Genome browser will be placed here
ACMG classification
Verdict is Uncertain_significance. Variant got 4 ACMG points.
Transcripts
RefSeq
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
GNE | ENST00000396594.8 | c.815T>G | p.Ile272Ser | missense_variant | Exon 4 of 12 | 1 | NM_001128227.3 | ENSP00000379839.3 | ||
GNE | ENST00000642385.2 | c.722T>G | p.Ile241Ser | missense_variant | Exon 4 of 12 | NM_005476.7 | ENSP00000494141.2 |
Frequencies
GnomAD3 genomes AF: 0.00000657 AC: 1AN: 152256Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.00000795 AC: 2AN: 251438Hom.: 0 AF XY: 0.0000147 AC XY: 2AN XY: 135890
GnomAD4 exome AF: 0.00000137 AC: 2AN: 1461274Hom.: 0 Cov.: 30 AF XY: 0.00000138 AC XY: 1AN XY: 727024
GnomAD4 genome AF: 0.00000657 AC: 1AN: 152256Hom.: 0 Cov.: 32 AF XY: 0.0000134 AC XY: 1AN XY: 74394
ClinVar
Submissions by phenotype
GNE myopathy Pathogenic:2
- -
Variant summary: GNE c.815T>G (p.Ile272Ser) results in a non-conservative amino acid change located in the UDP-N-acetylglucosamine 2-epimerase domain 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 8e-06 in 251438 control chromosomes. c.815T>G has been reported in the literature in multiple individuals affected with GNE myopathy (example, Celeste_2014, Li_2011, Lv_2022). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 24796702, 21307865, 35138478). ClinVar contains an entry for this variant (Variation ID: 552257). Based on the evidence outlined above, the variant was classified as pathogenic. -
Sialuria;C1853926:GNE myopathy Pathogenic:1
This sequence change replaces isoleucine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 272 of the GNE protein (p.Ile272Ser). This variant is present in population databases (rs759945787, gnomAD 0.006%). This missense change has been observed in individual(s) with rimmed vacuolar distal myopathy (PMID: 15834044, 17098358). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. This variant is also known as Ile241Ser. ClinVar contains an entry for this variant (Variation ID: 552257). 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. -
not provided Uncertain:1
- -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at