rs1236647498

Positions:

• chr9-36249276-G-A

Variant summary

Our verdict is Pathogenic. Variant got 19 ACMG points: 19P and 0B. PM1 PM2 PM5 PP2 PP3_Strong PP5_Very_Strong

The NM_005476.7(GNE):​c.80C>T​(p.Pro27Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000342 in 1,461,754 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 (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P27S) has been classified as Pathogenic.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000034 (0 hom.)
• Consequence: GNE NM_005476.7 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:6
• Conservation: PhyloP100: 8.91

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 19 ACMG points.

• PM1: In a helix (size 14) in uniprot entity GLCNE_HUMAN there are 4 pathogenic changes around while only 0 benign (100%) in NM_005476.7
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr9-36249277-G-A is described in Lovd as [Pathogenic].
• 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.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.939
• PP5: Variant 9-36249276-G-A is Pathogenic according to our data. Variant chr9-36249276-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 551266.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-36249276-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GNE	NM_001128227.3	c.173C>T	p.Pro58Leu	missense_variant	2/12	ENST00000396594.8	NP_001121699.1
GNE	NM_005476.7	c.80C>T	p.Pro27Leu	missense_variant	2/12	ENST00000642385.2	NP_005467.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GNE	ENST00000396594.8	c.173C>T	p.Pro58Leu	missense_variant	2/12	1	NM_001128227.3	ENSP00000379839.3
GNE	ENST00000642385.2	c.80C>T	p.Pro27Leu	missense_variant	2/12		NM_005476.7	ENSP00000494141.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000342 AC: 5 AN: 1461754 Hom.: 0 Cov.: 31 AF XY: 0.00000550 AC XY: 4 AN XY: 727184

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: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000450

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Alfa AF: 0.000224 Hom.: 0

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

GNE myopathy Pathogenic:4

Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Dec 02, 2023	- -
Likely pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Apr 20, 2021	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Counsyl	Mar 28, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jun 30, 2023	Variant summary: GNE c.173C>T (p.Pro58Leu) results in a non-conservative amino acid change located in the UDP-N-acetylglucosamine 2-epimerase domain (IPR003331) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251478 control chromosomes (gnomAD v2.1, Exomes dataset). c.173C>T has been reported in the literature in multiple compound heterozygous individuals affected with Inclusion Body Myopathy 2 (e.g., Mori-Yoshimura_2012, Cho_2014, Zhao_2015, Murtazina_2022). These data indicate that the variant is very likely to be associated with disease. The following publications have been ascertained in the context of this evaluation (PMID: 24027297, 22507750, 36360228, 25986339). Four submitters have reported clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as pathogenic (n = 1) or likely pathogenic (n = 3). Based on the evidence outlined above, the variant was classified as pathogenic. -

Sialuria;C1853926:GNE myopathy Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Oct 05, 2022

For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Pro58 amino acid residue in GNE. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 21708040, 27829678, 28717665). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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. ClinVar contains an entry for this variant (Variation ID: 551266). This missense change has been observed in individuals with autosomal recessive GNE-related myopathy (PMID: 22507750, 24005727, 24027297). This variant is present in population databases (no rsID available, gnomAD 0.007%). This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 58 of the GNE protein (p.Pro58Leu). -

not provided Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Revvity Omics, Revvity

Jun 29, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.84
BayesDel_addAF	Pathogenic	0.50	D
BayesDel_noAF	Pathogenic	0.48
CADD	Pathogenic	28
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.86	D;.;D;.;D
Eigen	Uncertain	0.34
Eigen_PC	Uncertain	0.44
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Pathogenic	0.99	.;D;D;D;.
M_CAP	Pathogenic	0.73	D
MetaRNN	Pathogenic	0.94	D;D;D;D;D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Benign	0.90	L;.;L;L;L
PrimateAI	Pathogenic	0.87	D
PROVEAN	Uncertain	-3.5	.;D;D;D;D
REVEL	Pathogenic	0.86
Sift	Benign	0.069	.;T;T;T;T
Sift4G	Uncertain	0.0040	.;D;D;D;D
Polyphen		0.80	P;P;P;.;P
Vest4		0.88, 0.90, 0.84, 0.90
MutPred		0.80		Loss of methylation at K24 (P = 0.0886);.;Loss of methylation at K24 (P = 0.0886);Loss of methylation at K24 (P = 0.0886);Loss of methylation at K24 (P = 0.0886);
MVP		0.97
MPC		0.86
ClinPred		0.98	D
GERP RS		4.8
Varity_R		0.70
gMVP		0.99

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: rs1236647498; hg19: chr9-36249273;