rs121908630

Variant names:

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PP2PP5

The NM_005476.7(GNE):c.673G>A(p.Asp225Asn) variant causes a missense change. The variant allele was found at a frequency of 0.00000435 in 1,610,818 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000027 ( 0 hom. )

Consequence

GNE
NM_005476.7 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:3U:2

Conservation

PhyloP100: 5.46

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]

GNE links:

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]

CLTA links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

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.

PP5

Variant 9-36236928-C-T is Pathogenic according to our data. Variant chr9-36236928-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 6031.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=2, Pathogenic=1, Likely_pathogenic=1}. Variant chr9-36236928-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GNE	NM_001128227.3 link	c.766G>A	p.Asp256Asn	missense_variant	Exon 4 of 12	ENST00000396594.8	NP_001121699.1	Q9Y223-2
GNE	NM_005476.7 link	c.673G>A	p.Asp225Asn	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
GNE	ENST00000396594.8 link	c.766G>A	p.Asp256Asn	missense_variant	Exon 4 of 12	1	NM_001128227.3	ENSP00000379839.3		Q9Y223-2
GNE	ENST00000642385.2 link	c.673G>A	p.Asp225Asn	missense_variant	Exon 4 of 12		NM_005476.7	ENSP00000494141.2		Q9Y223-1

Frequencies

GnomAD3 genomes

AF:

0.0000197

AC:

AN:

152170

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000724

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.00000274

AC:

AN:

1458648

Hom.:

Cov.:

AF XY:

0.00000276

AC XY:

AN XY:

725886

show subpopulations

Gnomad4 AFR exome

AF:

0.000120

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:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000197

AC:

AN:

152170

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74334

show subpopulations

Gnomad4 AFR

AF:

0.0000724

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000363

Hom.:

Bravo

AF:

0.0000189

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:3Uncertain:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

GNE myopathy

Pathogenic:2Uncertain:1

Likely pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Apr 05, 2022	Variant summary: GNE c.766G>A (p.Asp256Asn) results in a 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 benign effect of the variant on protein function. The variant was absent in 251392 control chromosomes. c.766G>A has been reported in the literature in four individuals affected with Inclusion Body Myopathy 2 from a single family, in the compound heterozygous state (Eisenberg_2001). These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Two submitters classified the variant as VUS while one classified as pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic. -
Pathogenic, no assertion criteria provided	literature only	OMIM	Sep 01, 2001	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Counsyl	May 24, 2017	- -

Sialuria;C1853926:GNE myopathy

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Nov 27, 2023

This sequence change replaces aspartic acid, which is acidic and polar, with asparagine, which is neutral and polar, at codon 256 of the GNE protein (p.Asp256Asn). This variant is present in population databases (rs121908630, gnomAD 0.02%). This missense change has been observed in individual(s) with GNE-related myopathy (PMID: 11528398). 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 D225N. ClinVar contains an entry for this variant (Variation ID: 6031). 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

Uncertain significance, criteria provided, single submitter

clinical testing

Eurofins Ntd Llc (ga)

Aug 28, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.083

BayesDel_addAF

Uncertain

0.087

BayesDel_noAF

Benign

-0.11

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.88

D;.;D;.;.;D

Eigen

Uncertain

0.38

Eigen_PC

Uncertain

0.52

FATHMM_MKL

Uncertain

0.96

LIST_S2

Uncertain

0.96

.;D;D;D;D;.

M_CAP

Pathogenic

0.67

MetaRNN

Uncertain

0.54

D;D;D;D;D;D

MetaSVM

Pathogenic

1.1

MutationAssessor

Benign

0.63

N;.;N;.;N;N

PrimateAI

Pathogenic

0.86

PROVEAN

Benign

-1.5

.;N;N;.;N;N

REVEL

Uncertain

0.56

Sift

Benign

0.27

.;T;T;.;T;T

Sift4G

Benign

0.18

.;T;T;T;T;T

Polyphen

0.0060

B;B;B;.;.;B

Vest4

0.33, 0.34, 0.35, 0.33

MVP

0.97

MPC

0.53

ClinPred

0.75

GERP RS

6.1

Varity_R

0.42

gMVP

0.89

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over