rs769716748

Variant summary

Our verdict is Pathogenic. The variant received 19 ACMG points: 19P and 0B. PS3PM5PP2PP3_StrongPP5_Very_Strong

The NM_005476.7(GNE):​c.31C>T​(p.Arg11Trp) variant causes a missense change. The variant allele was found at a frequency of 0.00000684 in 1,461,544 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 (★★). ClinVar reports functional evidence for this variant: "SCV003441378: Experimental studies have shown that this missense change affects GNE function (PMID:16503651).". Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R11Q) has been classified as Likely pathogenic.

Frequency

Genomes: not found (cov: 32)
Exomes 𝑓: 0.0000068 ( 0 hom. )

Consequence

GNE
NM_005476.7 missense

Scores

10
7
1

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:5

Conservation

PhyloP100: 4.38

Publications

7 publications found
Variant links:
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 19 ACMG points.

PS3
PS3 evidence extracted from ClinVar submissions: SCV003441378: Experimental studies have shown that this missense change affects GNE function (PMID: 16503651).
PM5
Other missense variant is known to change same aminoacid residue: Variant chr9-36249324-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 596639.
PP2
Missense variant in the GNE gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 44 curated pathogenic missense variants (we use a threshold of 10). The gene has 1 curated benign missense variants. Gene score misZ: 2.5904 (below the threshold of 3.09). Trascript score misZ: 3.9915 (above the threshold of 3.09). GenCC associations: The gene is linked to GNE myopathy, sialuria, macrothrombocytopenia, isolated, congenital myopathy, platelet-type bleeding disorder 19.
PP3
MetaRNN computational evidence supports a deleterious effect, 0.962
PP5
Variant 9-36249325-G-A is Pathogenic according to our data. Variant chr9-36249325-G-A is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 550820.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005476.7. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.
GeneTranscriptTagsHGVScHGVSpEffectExon RankProteinUniProt
GNE
NM_001128227.3
MANE Plus Clinical
c.124C>Tp.Arg42Trp
missense
Exon 2 of 12NP_001121699.1Q9Y223-2
GNE
NM_005476.7
MANE Select
c.31C>Tp.Arg11Trp
missense
Exon 2 of 12NP_005467.1Q9Y223-1
GNE
NM_001374797.1
c.31C>Tp.Arg11Trp
missense
Exon 2 of 11NP_001361726.1

Ensembl Transcripts

Sel.
GeneTranscriptTagsHGVScHGVSpEffectExon RankProteinUniProt
GNE
ENST00000396594.8
TSL:1 MANE Plus Clinical
c.124C>Tp.Arg42Trp
missense
Exon 2 of 12ENSP00000379839.3Q9Y223-2
GNE
ENST00000642385.2
MANE Select
c.31C>Tp.Arg11Trp
missense
Exon 2 of 12ENSP00000494141.2Q9Y223-1
GNE
ENST00000543356.7
TSL:1
c.-13-2843C>T
intron
N/AENSP00000437765.3A0A7I2SU25

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD2 exomes
AF:
0.00000796
AC:
2
AN:
251362
AF XY:
0.00000736
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.0000289
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00000880
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.00000684
AC:
10
AN:
1461544
Hom.:
0
Cov.:
31
AF XY:
0.00000550
AC XY:
4
AN XY:
727100
show subpopulations
African (AFR)
AF:
0.00
AC:
0
AN:
33474
American (AMR)
AF:
0.0000224
AC:
1
AN:
44722
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
26130
East Asian (EAS)
AF:
0.00
AC:
0
AN:
39696
South Asian (SAS)
AF:
0.00
AC:
0
AN:
86244
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
53418
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
5766
European-Non Finnish (NFE)
AF:
0.00000810
AC:
9
AN:
1111716
Other (OTH)
AF:
0.00
AC:
0
AN:
60378
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.480
Heterozygous variant carriers
0
1
1
2
2
3
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Exome Het
Variant carriers
0
2
4
6
8
10
<30
30-35
35-40
40-45
45-50
50-55
55-60
60-65
65-70
70-75
75-80
>80
Age
GnomAD4 genome
Cov.:
32
ExAC
AF:
0.00000824
AC:
1

ClinVar

ClinVar submissions
Significance:Pathogenic/Likely pathogenic
Revision:criteria provided, multiple submitters, no conflicts
View on ClinVar
Pathogenic
VUS
Benign
Condition
3
-
-
GNE myopathy (3)
1
-
-
not provided (1)
1
-
-
Sialuria;C1853926:GNE myopathy (1)

Computational scores

Source: dbNSFP v4.9

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Uncertain
0.52
BayesDel_addAF
Pathogenic
0.43
D
BayesDel_noAF
Pathogenic
0.47
CADD
Pathogenic
33
DANN
Pathogenic
1.0
DEOGEN2
Pathogenic
0.92
D
Eigen
Uncertain
0.52
Eigen_PC
Uncertain
0.54
FATHMM_MKL
Uncertain
0.93
D
LIST_S2
Uncertain
0.91
D
M_CAP
Pathogenic
0.57
D
MetaRNN
Pathogenic
0.96
D
MetaSVM
Pathogenic
1.0
D
MutationAssessor
Benign
0.69
N
PhyloP100
4.4
PrimateAI
Pathogenic
0.83
D
PROVEAN
Uncertain
-3.7
D
REVEL
Pathogenic
0.83
Sift
Pathogenic
0.0
D
Sift4G
Uncertain
0.0050
D
Polyphen
1.0
D
Vest4
0.87
MutPred
0.89
Loss of MoRF binding (P = 0.0237)
MVP
0.99
MPC
1.3
ClinPred
0.98
D
GERP RS
4.2
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.1
Varity_R
0.71
gMVP
0.97
Mutation Taster
=0/100
disease causing (ClinVar)

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.010
Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

Other links and lift over

dbSNP: rs769716748; hg19: chr9-36249322; COSMIC: COSV64952198; API
For research and educational, non-commercial use only. Not for clinical or diagnostic use. GeneBe does not provide medical advice. Data use for AI modeling is prohibited: if used, the cost is $0.001 per byte of downloaded uncompressed data.