rs886042585

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM2PP2PP3_Moderate

The NM_005476.7(GNE):​c.748C>A​(p.Leu250Met) variant causes a missense change. The variant allele was found at a frequency of 0.000000684 in 1,461,578 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 (★★).

Frequency

Genomes: not found (cov: 33)
Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

GNE
NM_005476.7 missense

Scores

11
5
3

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:3

Conservation

PhyloP100: 6.04
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 made for transcript

Verdict is Uncertain_significance. Variant got 5 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
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 macrothrombocytopenia, isolated, platelet-type bleeding disorder 19, sialuria, GNE myopathy.
PP3
MetaRNN computational evidence supports a deleterious effect, 0.889

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
GNENM_001128227.3 linkc.841C>A p.Leu281Met missense_variant Exon 4 of 12 ENST00000396594.8 NP_001121699.1 Q9Y223-2
GNENM_005476.7 linkc.748C>A p.Leu250Met missense_variant Exon 4 of 12 ENST00000642385.2 NP_005467.1 Q9Y223-1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
GNEENST00000396594.8 linkc.841C>A p.Leu281Met missense_variant Exon 4 of 12 1 NM_001128227.3 ENSP00000379839.3 Q9Y223-2
GNEENST00000642385.2 linkc.748C>A p.Leu250Met missense_variant Exon 4 of 12 NM_005476.7 ENSP00000494141.2 Q9Y223-1

Frequencies

GnomAD3 genomes
Cov.:
33
GnomAD3 exomes
AF:
0.00000398
AC:
1
AN:
251416
Hom.:
0
AF XY:
0.00
AC XY:
0
AN XY:
135880
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00000879
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
6.84e-7
AC:
1
AN:
1461578
Hom.:
0
Cov.:
30
AF XY:
0.00
AC XY:
0
AN XY:
727102
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
8.99e-7
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
33
Bravo
AF:
0.00000378

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:3
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not specified Uncertain:1
Aug 01, 2024
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

Variant summary: GNE c.841C>A (p.Leu281Met) results in a conservative amino acid change located in the UDP-N-acetylglucosamine 2-epimerase domain (IPR003331) of the encoded protein sequence. Four 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 251416 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.841C>A has been reported in the literature in the presumed compound heterozygous state in at least 1 individual affected with clinical features of autosomal recessive Inclusion Body Myopathy 2 (example, Chaouch_2014). These report(s) do not provide unequivocal conclusions about association of the variant with GNE-related conditions. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication has been ascertained in the context of this evaluation (PMID: 24695763). ClinVar contains an entry for this variant (Variation ID: 283249). Based on the evidence outlined above, the variant was classified as uncertain significance. -

GNE myopathy Uncertain:1
Apr 21, 2017
Counsyl
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

not provided Uncertain:1
Sep 10, 2015
Eurofins Ntd Llc (ga)
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Uncertain
0.47
BayesDel_addAF
Pathogenic
0.33
D
BayesDel_noAF
Pathogenic
0.24
CADD
Pathogenic
27
DANN
Uncertain
1.0
DEOGEN2
Pathogenic
0.85
D;.;D;.;.;D
Eigen
Pathogenic
0.83
Eigen_PC
Pathogenic
0.83
FATHMM_MKL
Pathogenic
0.99
D
LIST_S2
Uncertain
0.96
.;D;D;D;D;.
M_CAP
Pathogenic
0.94
D
MetaRNN
Pathogenic
0.89
D;D;D;D;D;D
MetaSVM
Pathogenic
1.1
D
MutationAssessor
Benign
1.6
L;.;L;.;L;L
PrimateAI
Pathogenic
0.81
D
PROVEAN
Benign
-0.87
.;N;N;.;N;N
REVEL
Pathogenic
0.88
Sift
Uncertain
0.011
.;D;D;.;D;D
Sift4G
Uncertain
0.019
.;D;D;D;D;D
Polyphen
1.0
D;D;D;.;.;D
Vest4
0.82, 0.84, 0.76, 0.78
MutPred
0.65
Gain of methylation at K245 (P = 0.0696);.;Gain of methylation at K245 (P = 0.0696);.;Gain of methylation at K245 (P = 0.0696);Gain of methylation at K245 (P = 0.0696);
MVP
0.97
MPC
1.4
ClinPred
0.81
D
GERP RS
6.1
Varity_R
0.81
gMVP
0.75

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.0
Details are displayed if max score is > 0.2

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs886042585; hg19: chr9-36236850; API