rs1554668704
Variant names:
Variant summary
Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PVS1PM2
The NM_001128227.3(GNE):c.3G>A(p.Met1?) variant causes a start lost change. The variant allele was found at a frequency of 0.000000685 in 1,460,908 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 Uncertain significance (no stars).
Frequency
Genomes: not found (cov: 31)
Exomes 𝑓: 6.8e-7 ( 0 hom. )
Consequence
GNE
NM_001128227.3 start_lost
NM_001128227.3 start_lost
Scores
2
7
4
Clinical Significance
Conservation
PhyloP100: 3.80
Publications
0 publications found
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]
Genome browser will be placed here
ACMG classification
Classification was made for transcript
Our verdict: Pathogenic. The variant received 10 ACMG points.
PVS1
Start lost variant, next in-frame start position is after 7 pathogenic variants. Next in-frame start position is after 32 codons. Genomic position: 36249355. Lost 0.042 part of the original CDS.
PM2
Very rare variant in population databases, with high coverage;
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|
| GNE | NM_001128227.3 | c.3G>A | p.Met1? | start_lost | Exon 1 of 12 | ENST00000396594.8 | NP_001121699.1 | |
| GNE | XM_005251334.5 | c.3G>A | p.Met1? | start_lost | Exon 1 of 11 | XP_005251391.1 | ||
| GNE | NM_001190388.2 | c.-62G>A | 5_prime_UTR_variant | Exon 1 of 11 | NP_001177317.2 | |||
| LOC124902150 | XR_007061473.1 | n.297-7766C>T | intron_variant | Intron 2 of 2 |
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|---|
| GNE | ENST00000396594.8 | c.3G>A | p.Met1? | start_lost | Exon 1 of 12 | 1 | NM_001128227.3 | ENSP00000379839.3 | ||
| GNE | ENST00000543356.7 | c.-62G>A | 5_prime_UTR_variant | Exon 1 of 11 | 1 | ENSP00000437765.3 | ||||
| GNE | ENST00000644762.1 | n.35G>A | non_coding_transcript_exon_variant | Exon 1 of 2 | ||||||
| CLTA | ENST00000464497.5 | n.*101+11368C>T | intron_variant | Intron 6 of 7 | 5 | ENSP00000419158.1 |
Frequencies
GnomAD3 genomes
GnomAD3 genomes
Cov.:
31
GnomAD4 exome AF: 6.85e-7 AC: 1AN: 1460908Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0AN XY: 726784 show subpopulations ⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.
GnomAD4 exome
AF:
AC:
1
AN:
1460908
Hom.:
Cov.:
30
AF XY:
AC XY:
0
AN XY:
726784
show subpopulations
⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.
African (AFR)
AF:
AC:
0
AN:
33448
American (AMR)
AF:
AC:
0
AN:
44646
Ashkenazi Jewish (ASJ)
AF:
AC:
0
AN:
26124
East Asian (EAS)
AF:
AC:
0
AN:
39656
South Asian (SAS)
AF:
AC:
0
AN:
86154
European-Finnish (FIN)
AF:
AC:
0
AN:
53402
Middle Eastern (MID)
AF:
AC:
0
AN:
5764
European-Non Finnish (NFE)
AF:
AC:
1
AN:
1111382
Other (OTH)
AF:
AC:
0
AN:
60332
⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.275
Heterozygous variant carriers
0
0
1
1
2
2
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance
GnomAD4 genome
GnomAD4 genome
Cov.:
31
ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: no assertion criteria provided
LINK: link
Submissions by phenotype
GNE myopathy Uncertain:1
Nov 19, 2017
Counsyl
Significance:Uncertain significance
Review Status:no assertion criteria provided
Collection Method:clinical testing
This submission and the accompanying classification are no longer maintained by the submitter. For more information on current observations and classification, please contact variantquestions@myriad.com. -
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Uncertain
DANN
Uncertain
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Uncertain
D
LIST_S2
Uncertain
D
MetaRNN
Pathogenic
D
MetaSVM
Benign
T
PhyloP100
PROVEAN
Benign
N
REVEL
Uncertain
Sift
Benign
T
Polyphen
P
Vest4
MutPred
Gain of catalytic residue at M1 (P = 0.0254);
MVP
ClinPred
D
GERP RS
gMVP
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at
Publications
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