rs121908627

chr9-36217448-C-Achr9-36217448-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 3P and 3B. PM5 PP2 BP4_Moderate BP6

The NM_001128227.3(GNE):c.2179G>T(p.Val727Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00135 in 1,614,204 control chromosomes in the GnomAD database, including 9 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V727M) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: 𝑓 0.00080 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0014 (9 hom.)
• Consequence: GNE NM_001128227.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:11 B:3
• Conservation: PhyloP100: 7.52

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM5: Other missense variant is known to change same aminoacid residue: Variant chr9-36217448-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 6028.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=4, Pathogenic=14, Likely_benign=1, not_provided=1}.
• PP2: Missense variant where missense usually causes diseases, GNE
• BP4: Computational evidence support a benign effect (MetaRNN=0.07420033).
• BP6: Variant 9-36217448-C-A is Benign according to our data. Variant chr9-36217448-C-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 194025.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=8, Likely_benign=3}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GNE	NM_001128227.3	c.2179G>T	p.Val727Leu	missense_variant	12/12	ENST00000396594.8
GNE	NM_005476.7	c.2086G>T	p.Val696Leu	missense_variant	12/12	ENST00000642385.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GNE	ENST00000396594.8	c.2179G>T	p.Val727Leu	missense_variant	12/12	1	NM_001128227.3
GNE	ENST00000642385.2	c.2086G>T	p.Val696Leu	missense_variant	12/12		NM_005476.7	P1

Frequencies

GnomAD3 genomes AF: 0.000802 AC: 122 AN: 152208 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000196

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00104

Gnomad FIN AF: 0.000188

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00148

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.000895 AC: 225 AN: 251452 Hom.: 0 AF XY: 0.000927 AC XY: 126 AN XY: 135898

Gnomad AFR exome AF: 0.000369

Gnomad AMR exome AF: 0.000376

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000915

Gnomad FIN exome AF: 0.000277

Gnomad NFE exome AF: 0.00145

Gnomad OTH exome AF: 0.00114

GnomAD4 exome AF: 0.00141 AC: 2065 AN: 1461878 Hom.: 9 Cov.: 31 AF XY: 0.00139 AC XY: 1009 AN XY: 727240

Gnomad4 AFR exome AF: 0.000239

Gnomad4 AMR exome AF: 0.000335

Gnomad4 ASJ exome AF: 0.0000383

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00130

Gnomad4 FIN exome AF: 0.000300

Gnomad4 NFE exome AF: 0.00163

Gnomad4 OTH exome AF: 0.00157

GnomAD4 genome AF: 0.000801 AC: 122 AN: 152326 Hom.: 0 Cov.: 32 AF XY: 0.000738 AC XY: 55 AN XY: 74490

Gnomad4 AFR AF: 0.000241

Gnomad4 AMR AF: 0.000196

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00104

Gnomad4 FIN AF: 0.000188

Gnomad4 NFE AF: 0.00148

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.00116 Hom.: 1

Bravo AF: 0.000691

TwinsUK AF: 0.00162 AC: 6

ALSPAC AF: 0.00337 AC: 13

ESP6500AA AF: 0.000454 AC: 2

ESP6500EA AF: 0.00174 AC: 15

ExAC AF: 0.000964 AC: 117

EpiCase AF: 0.00153

EpiControl AF: 0.00154

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:11 Benign:3

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:8

Uncertain significance, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Uncertain significance, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Apr 11, 2022	Reported as likely non-disease causing variant as it was identified in control populations and in silico analysis predicted the variant had nondamaging/mildly severe effect on GNE protein (Celeste et al., 2014); Missense variants in this gene are often considered pathogenic (HGMD); In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 30564623, 24796702, 28468868, 32759194) -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Dec 27, 2016	- -
Uncertain significance, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Mar 01, 2024	GNE: PM5 -
Uncertain significance, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Dec 06, 2022	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Nov 08, 2016	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Nov 02, 2021	- -

GNE myopathy Uncertain:1 Benign:1

Uncertain significance, no assertion criteria provided	clinical testing	Natera, Inc.	Jan 12, 2020	- -
Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jun 14, 2016	- -

Sialuria;C1853926:GNE myopathy Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Oct 31, 2022

This sequence change replaces valine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 727 of the GNE protein (p.Val727Leu). This variant is present in population databases (rs121908627, gnomAD 0.1%), and has an allele count higher than expected for a pathogenic variant. This variant has not been reported in the literature in individuals affected with GNE-related conditions. ClinVar contains an entry for this variant (Variation ID: 194025). 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. This variant disrupts the p.Val727 amino acid residue in GNE. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 11528398, 12497639, 20175955, 21708040, 24005727, 25182749). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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-related disorder Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Apr 26, 2023

The GNE c.2179G>T variant is predicted to result in the amino acid substitution p.Val727Leu. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.15% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/9-36217445-C-A). Although we suspect that this variant may be benign, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Sialuria Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 2017

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

Inclusion Body Myopathy, Recessive Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.39
BayesDel_addAF	Uncertain	0.013	T
BayesDel_noAF	Pathogenic	0.24
Cadd	Benign	19
Dann	Uncertain	0.99
DEOGEN2	Uncertain	0.68	D;.;D;.;.;.;D
Eigen	Benign	0.14
Eigen_PC	Uncertain	0.32
FATHMM_MKL	Pathogenic	0.99	D
M_CAP	Uncertain	0.19	D
MetaRNN	Benign	0.074	T;T;T;T;T;T;T
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Benign	1.5	L;.;L;.;.;.;L
MutationTaster	Benign	1.0	D;D;D;D;D;D
PrimateAI	Uncertain	0.58	T
Polyphen		0.022	B;B;B;.;.;.;B
Vest4		0.62, 0.63, 0.60, 0.60, 0.59, 0.64
MutPred		0.56		Loss of sheet (P = 0.0037);.;Loss of sheet (P = 0.0037);.;.;.;Loss of sheet (P = 0.0037);
MVP		0.95
MPC		0.56
ClinPred		0.026	T
GERP RS		5.7
Varity_R		0.57
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

Other links and lift over

dbSNP: rs121908627; hg19: chr9-36217445;