rs776384541

Positions:

• chr9-36217529-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM1 PP2 PP3 PP5

The NM_001128227.3(GNE):​c.2098G>A​(p.Gly700Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000151 in 1,461,780 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 13/23 in silico tools predict a damaging 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. G700G) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000015 (0 hom.)
• Consequence: GNE NM_001128227.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2 U:4
• 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 5 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 7 uncertain in NM_001128227.3
• 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 4.032 (greater than threshold 3.09). GenCC has associacion of gene with macrothrombocytopenia, isolated, platelet-type bleeding disorder 19, sialuria, GNE myopathy.
• PP3: Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
• PP5: Variant 9-36217529-C-T is Pathogenic according to our data. Variant chr9-36217529-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 290224.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=3, Likely_pathogenic=1, Pathogenic=1}. Variant chr9-36217529-C-T is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GNE	NM_001128227.3	c.2098G>A	p.Gly700Arg	missense_variant	12/12	ENST00000396594.8
GNE	NM_005476.7	c.2005G>A	p.Gly669Arg	missense_variant	12/12	ENST00000642385.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GNE	ENST00000396594.8	c.2098G>A	p.Gly700Arg	missense_variant	12/12	1	NM_001128227.3
GNE	ENST00000642385.2	c.2005G>A	p.Gly669Arg	missense_variant	12/12		NM_005476.7	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.0000199 AC: 5 AN: 251470 Hom.: 0 AF XY: 0.0000294 AC XY: 4 AN XY: 135910

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000867

Gnomad ASJ exome AF: 0.0000992

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: 0.0000151 AC: 22 AN: 1461780 Hom.: 0 Cov.: 31 AF XY: 0.0000165 AC XY: 12 AN XY: 727190

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000671

Gnomad4 ASJ exome AF: 0.0000383

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000144

Gnomad4 OTH exome AF: 0.0000331

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000688 Hom.: 0

Bravo AF: 0.00000756

ExAC AF: 0.0000247 AC: 3

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:2 Uncertain:4

Revision: criteria provided, conflicting classifications

Submissions by phenotype

GNE myopathy Pathogenic:1 Uncertain:1

Uncertain significance, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Diagnostics Services (NGS), CSIR - Centre For Cellular And Molecular Biology	Feb 02, 2023	The c.2005G>A variant is not present in publicly available population databases like 1000 Genomes, EVS, Indian Exome Database or our in-house exome database. The variant is present in ExAC and gnomAD at low frequencies. This variant has been previously observed in affected individuals, published in literature [PMID:23437777; PMID:27858732; PMID:19917666; PMID:29941673] and reported to HGMD (ID: CM134919). It has been reported to the ClinVar database (Accession ID: VCV000290224.7) as ‘Uncertain significance’ by multiple submitters. In silico pathogenicity prediction programs like SIFT, PolyPhen-2, MutationTaster2, CADD, Varsome etc predicted this variant to be likely deleterious. The variant is located in a mutational hotspot region of the gene. This individual harbours another heterozygous variant (c.1609T>C) in GNE gene. -

not provided Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	May 23, 2017	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Jun 25, 2022	- -

Sialuria;C1853926:GNE myopathy Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Oct 17, 2023

This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 700 of the GNE protein (p.Gly700Arg). This variant is present in population databases (rs776384541, gnomAD 0.01%). This missense change has been observed in individual(s) with clinical features of autosomal recessive distal myopathy (PMID: 23437777, 24027297, 29480215; Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is also known as p.Gly669Arg. ClinVar contains an entry for this variant (Variation ID: 290224). 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. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. For these reasons, this variant has been classified as Pathogenic. -

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

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

Jan 17, 2023

Variant summary: GNE c.2098G>A (p.Gly700Arg) results in a non-conservative amino acid change located in the ATPase, nucleotide binding domain (IPR043129) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 2e-05 in 251470 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.2098G>A has been reported in the literature as a presumed compound heterozygous genotype in at-least one individual with features of Hereditary Inclusion Body Myopathy (example, No_2013). These data do not allow any conclusion about variant significance. 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. All laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Pathogenic	0.43	D
BayesDel_noAF	Pathogenic	0.58
CADD	Pathogenic	35
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.91	D;.;D;.;.;.;D
Eigen	Pathogenic	0.90
Eigen_PC	Pathogenic	0.86
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.98	.;D;D;D;D;D;.
M_CAP	Pathogenic	0.85	D
MetaRNN	Pathogenic	0.97	D;D;D;D;D;D;D
MetaSVM	Pathogenic	0.87	D
MutationAssessor	Pathogenic	3.4	M;.;M;.;.;.;M
MutationTaster	Benign	1.0	D;D;D;D;D;D
PrimateAI	Pathogenic	0.86	D
PROVEAN	Benign	-1.7	.;N;N;.;D;N;N
REVEL	Pathogenic	0.92
Sift	Pathogenic	0.0	.;D;D;.;D;D;D
Sift4G	Pathogenic	0.0	.;D;D;D;D;D;D
Polyphen		1.0	D;D;D;.;.;.;D
Vest4		0.99, 0.99, 0.98, 0.99, 0.98, 1.0
MutPred		0.89		Loss of glycosylation at S668 (P = 0.0464);.;Loss of glycosylation at S668 (P = 0.0464);.;.;.;Loss of glycosylation at S668 (P = 0.0464);
MVP		0.96
MPC		1.6
ClinPred		0.96	D
GERP RS		5.6
Varity_R		0.94
gMVP		0.98

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.59		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.59		Position offset: -2

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

Publications

LitVar

Other links and lift over

dbSNP: rs776384541; hg19: chr9-36217526;