rs369328625

Positions:

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PP2PP5BP4

The NM_005476.7(GNE):c.598A>T(p.Ile200Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000108 in 1,613,940 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. I200I) has been classified as Benign.

Frequency

Genomes: 𝑓 0.000039 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00012 ( 0 hom. )

Consequence

GNE
NM_005476.7 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:3U:4

Conservation

PhyloP100: 1.41

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 1 ACMG points.

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 3.9915 (greater than threshold 3.09). GenCC has associacion of gene with macrothrombocytopenia, isolated, platelet-type bleeding disorder 19, sialuria, GNE myopathy.

PP5

Variant 9-36246049-T-A is Pathogenic according to our data. Variant chr9-36246049-T-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 558623.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=5, Likely_pathogenic=2}. Variant chr9-36246049-T-A is described in Lovd as [Pathogenic].

BP4

Computational evidence support a benign effect (MetaRNN=0.29317367). . Strength limited to SUPPORTING due to the PP5.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GNE	NM_001128227.3 linkuse as main transcript	c.691A>T	p.Ile231Phe	missense_variant	3/12	ENST00000396594.8	NP_001121699.1	Q9Y223-2
GNE	NM_005476.7 linkuse as main transcript	c.598A>T	p.Ile200Phe	missense_variant	3/12	ENST00000642385.2	NP_005467.1	Q9Y223-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GNE	ENST00000396594.8 linkuse as main transcript	c.691A>T	p.Ile231Phe	missense_variant	3/12	1	NM_001128227.3	ENSP00000379839.3		Q9Y223-2
GNE	ENST00000642385.2 linkuse as main transcript	c.598A>T	p.Ile200Phe	missense_variant	3/12		NM_005476.7	ENSP00000494141.2		Q9Y223-1

Frequencies

GnomAD3 genomes

AF:

0.0000394

AC:

AN:

152270

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000654

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:

0.0000735

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000358

AC:

AN:

251334

Hom.:

AF XY:

0.0000368

AC XY:

AN XY:

135836

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000578

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:

0.0000528

Gnomad OTH exome

AF:

0.000163

GnomAD4 exome

AF:

0.000116

AC:

169

AN:

1461670

Hom.:

Cov.:

AF XY:

0.000105

AC XY:

AN XY:

727158

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000447

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:

0.000141

Gnomad4 OTH exome

AF:

0.000166

GnomAD4 genome

AF:

0.0000394

AC:

AN:

152270

Hom.:

Cov.:

AF XY:

0.0000403

AC XY:

AN XY:

74398

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.0000654

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000735

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000130

Hom.:

Bravo

AF:

0.0000680

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000259

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.0000330

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:3Uncertain:4

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Pathogenic:2Uncertain:1

Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Oct 25, 2023	Reported in the compound heterozygous state with other variants in the GNE gene in two unrelated patients with GNE myopathy in published literature (PMID: 24695763); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 19917666, 24796702, 12497639, 16503651, 29305133, 24695763) -
Likely pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Jun 17, 2019	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Aug 01, 2023	GNE: PM3:Very Strong, PM2:Supporting -

Sialuria;C1853926:GNE myopathy;C5935593:Thrombocytopenia 12 with or without myopathy

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Apr 18, 2024

- -

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

May 29, 2024

Variant summary: GNE c.691A>T (p.Ile231Phe), also referred to as p.Ile200Phe in the literature, results in a non-conservative amino acid change located in the UDP-N-acetylglucosamine 2-epimerase domain (IPR003331) of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 3.6e-05 in 251334 control chromosomes. c.691A>T has been reported in the literature in the compound heterozygous state in at least two individuals affected with Inclusion Body Myopathy (e.g. Eisenberg_2003, Chaouch_2014, Pogoryelova_2018). These data indicate that the variant may be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function and showed little to no damaging effect of this variant on UDP-GlcNAc 2-epimerase activity compared to the wild type protein (Penner_2006). The following publications have been ascertained in the context of this evaluation (PMID: 12497639, 24695763, 29305133, 16503651). ClinVar contains an entry for this variant (Variation ID: 558623). Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic. -

Sialuria;C1853926:GNE myopathy

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Dec 21, 2023

This sequence change replaces isoleucine, which is neutral and non-polar, with phenylalanine, which is neutral and non-polar, at codon 231 of the GNE protein (p.Ile231Phe). This variant is present in population databases (rs369328625, gnomAD 0.01%). This missense change has been observed in individuals with inclusion body myopathy (PMID: 12497639, 24695763, 29305133). This variant is also known as Ile200Phe. ClinVar contains an entry for this variant (Variation ID: 558623). 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. Experimental studies have shown that this missense change does not substantially affect GNE function (PMID: 16503651). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

GNE myopathy

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Counsyl

Jun 04, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.35

BayesDel_addAF

Pathogenic

0.20

BayesDel_noAF

Pathogenic

0.23

CADD

Benign

DANN

Benign

0.95

DEOGEN2

Pathogenic

0.88

D;.;D;.;.;.;D

Eigen

Benign

-0.14

Eigen_PC

Benign

-0.0037

FATHMM_MKL

Uncertain

0.96

LIST_S2

Uncertain

0.96

.;D;D;D;D;D;.

M_CAP

Pathogenic

0.49

MetaRNN

Benign

0.29

T;T;T;T;T;T;T

MetaSVM

Pathogenic

0.87

MutationAssessor

Benign

0.55

N;.;N;.;.;N;N

PrimateAI

Uncertain

0.52

PROVEAN

Benign

-1.0

.;N;N;.;N;N;N

REVEL

Pathogenic

0.67

Sift

Benign

0.071

.;T;T;.;D;T;T

Sift4G

Uncertain

0.018

.;D;D;D;T;D;D

Polyphen

0.32

B;B;B;.;.;.;B

Vest4

0.81, 0.85, 0.80, 0.73, 0.65

MVP

0.99

MPC

1.1

ClinPred

0.061

GERP RS

4.4

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.47

gMVP

0.77

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