rs752286512

Positions:

• chr9-36219883-C-T

Variant summary

Our verdict is Pathogenic. Variant got 13 ACMG points: 13P and 0B. PP2 PP3_Strong PP5_Very_Strong

The NM_001128227.3(GNE):​c.1864G>A​(p.Ala622Thr) variant causes a missense change. The variant allele was found at a frequency of 0.0000041 in 1,461,874 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 Likely pathogenic (★★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000041 (0 hom.)
• Consequence: GNE NM_001128227.3 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:2 U:1
• Conservation: PhyloP100: 5.48

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 Pathogenic. Variant got 13 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 4.032 (greater than threshold 3.09). GenCC has associacion of gene with macrothrombocytopenia, isolated, platelet-type bleeding disorder 19, sialuria, GNE myopathy.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.96
• PP5: Variant 9-36219883-C-T is Pathogenic according to our data. Variant chr9-36219883-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 498575.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-36219883-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GNE	NM_001128227.3	c.1864G>A	p.Ala622Thr	missense_variant	10/12	ENST00000396594.8	NP_001121699.1
GNE	NM_005476.7	c.1771G>A	p.Ala591Thr	missense_variant	10/12	ENST00000642385.2	NP_005467.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GNE	ENST00000396594.8	c.1864G>A	p.Ala622Thr	missense_variant	10/12	1	NM_001128227.3	ENSP00000379839
GNE	ENST00000642385.2	c.1771G>A	p.Ala591Thr	missense_variant	10/12		NM_005476.7	ENSP00000494141	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000795 AC: 2 AN: 251484 Hom.: 0 AF XY: 0.00000736 AC XY: 1 AN XY: 135916

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: 0.0000176

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000410 AC: 6 AN: 1461874 Hom.: 0 Cov.: 32 AF XY: 0.00000413 AC XY: 3 AN XY: 727238

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: 0.0000232

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000360

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ExAC AF: 0.0000165 AC: 2

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:2 Uncertain:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Sialuria;C1853926:GNE myopathy Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 14, 2023

For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Ala622 amino acid residue in GNE. Other variant(s) that disrupt this residue have been observed in individuals with GNE-related conditions (PMID: 30390020), which suggests that this may be a clinically significant amino acid residue. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. ClinVar contains an entry for this variant (Variation ID: 498575). This variant is also known as p.A591T. This missense change has been observed in individual(s) with autosomal recessive GNE-related conditions (PMID: 16372135, 21868336, 30390020, 31286697). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is present in population databases (rs752286512, gnomAD 0.002%). This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 622 of the GNE protein (p.Ala622Thr). -

GNE myopathy Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

Mar 30, 2023

- -

not provided Uncertain:1

Uncertain significance, flagged submission

clinical testing

Eurofins Ntd Llc (ga)

Dec 06, 2016

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.47
BayesDel_addAF	Pathogenic	0.50	D
BayesDel_noAF	Pathogenic	0.50
CADD	Pathogenic	29
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.80	D;.;D;.;.;.;D
Eigen	Uncertain	0.60
Eigen_PC	Uncertain	0.64
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Uncertain	0.97	.;D;D;D;D;D;.
M_CAP	Pathogenic	0.63	D
MetaRNN	Pathogenic	0.96	D;D;D;D;D;D;D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Uncertain	2.3	M;.;M;.;.;.;M
MutationTaster	Benign	1.0	D;D;D;D;D;D
PrimateAI	Uncertain	0.73	T
PROVEAN	Benign	-0.73	.;N;N;.;N;N;N
REVEL	Pathogenic	0.78
Sift	Uncertain	0.0010	.;D;D;.;D;D;D
Sift4G	Uncertain	0.010	.;D;D;D;D;D;D
Polyphen		0.96	D;D;D;.;.;.;D
Vest4		0.96, 0.96, 0.92, 0.94, 0.94
MutPred		0.94		Gain of phosphorylation at A591 (P = 0.1094);.;Gain of phosphorylation at A591 (P = 0.1094);.;.;.;Gain of phosphorylation at A591 (P = 0.1094);
MVP		0.97
MPC		1.0
ClinPred		0.77	D
GERP RS		5.8
Varity_R		0.76
gMVP		0.91

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs752286512; hg19: chr9-36219880; COSMIC: COSV64951273;