rs1554660090
Positions:
Variant summary
Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2PP2PP3_ModeratePP5
The NM_001128227.3(GNE):āc.1150A>Gā(p.Lys384Glu) variant causes a missense change. The variant allele was found at a frequency of 0.00000138 in 1,446,720 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 Conflicting classifications of pathogenicity (no stars).
Frequency
Genomes: not found (cov: 31)
Exomes š: 0.0000014 ( 0 hom. )
Consequence
GNE
NM_001128227.3 missense
NM_001128227.3 missense
Scores
9
6
4
Clinical Significance
Conservation
PhyloP100: 5.49
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 Likely_pathogenic. Variant got 6 ACMG points.
PM2
Very rare variant in population databases, with high coverage;
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 4.032 (greater than threshold 3.09). GenCC has associacion of gene with macrothrombocytopenia, isolated, platelet-type bleeding disorder 19, sialuria, GNE myopathy.
PP3
MetaRNN computational evidence supports a deleterious effect, 0.862
PP5
Variant 9-36229034-T-C is Pathogenic according to our data. Variant chr9-36229034-T-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 553464.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=1, Uncertain_significance=1}. Variant chr9-36229034-T-C is described in Lovd as [Pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
GNE | NM_001128227.3 | c.1150A>G | p.Lys384Glu | missense_variant | 6/12 | ENST00000396594.8 | NP_001121699.1 | |
GNE | NM_005476.7 | c.1057A>G | p.Lys353Glu | missense_variant | 6/12 | ENST00000642385.2 | NP_005467.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
GNE | ENST00000396594.8 | c.1150A>G | p.Lys384Glu | missense_variant | 6/12 | 1 | NM_001128227.3 | ENSP00000379839 | ||
GNE | ENST00000642385.2 | c.1057A>G | p.Lys353Glu | missense_variant | 6/12 | NM_005476.7 | ENSP00000494141 | P1 |
Frequencies
GnomAD3 genomes Cov.: 31
GnomAD3 genomes
Cov.:
31
GnomAD4 exome AF: 0.00000138 AC: 2AN: 1446720Hom.: 0 Cov.: 28 AF XY: 0.00000139 AC XY: 1AN XY: 720896
GnomAD4 exome
AF:
AC:
2
AN:
1446720
Hom.:
Cov.:
28
AF XY:
AC XY:
1
AN XY:
720896
Gnomad4 AFR exome
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GnomAD4 genome Cov.: 31
GnomAD4 genome
Cov.:
31
ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
GNE myopathy Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Counsyl | Aug 28, 2017 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Uncertain
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Uncertain
DEOGEN2
Pathogenic
D;.;D;.;.;.;D
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Pathogenic
D
LIST_S2
Uncertain
.;D;D;D;D;D;.
M_CAP
Pathogenic
D
MetaRNN
Pathogenic
D;D;D;D;D;D;D
MetaSVM
Pathogenic
D
MutationAssessor
Benign
L;.;L;.;.;L;L
MutationTaster
Benign
D;D;D;D;D;D
PrimateAI
Pathogenic
D
PROVEAN
Benign
.;N;N;.;N;N;N
REVEL
Pathogenic
Sift
Benign
.;T;T;.;D;T;T
Sift4G
Uncertain
.;D;T;T;T;T;T
Polyphen
D;P;D;.;.;.;D
Vest4
0.70, 0.71, 0.73, 0.69, 0.70
MutPred
Loss of ubiquitination at K353 (P = 0.0233);.;Loss of ubiquitination at K353 (P = 0.0233);.;.;Loss of ubiquitination at K353 (P = 0.0233);Loss of ubiquitination at K353 (P = 0.0233);
MVP
0.99
MPC
1.0
ClinPred
D
GERP RS
Varity_R
gMVP
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at