rs754892377

Positions:

• chr9-36222885-G-A

Variant summary

Our verdict is Pathogenic. Variant got 13 ACMG points: 13P and 0B. PM1 PM2 PP2 PP5_Very_Strong

The NM_001128227.3(GNE):​c.1618C>T​(p.His540Tyr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000274 in 1,461,810 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. H540P) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000027 (0 hom.)
• Consequence: GNE NM_001128227.3 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 7.38

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.

• 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
• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant where missense usually causes diseases, GNE
• PP5: Variant 9-36222885-G-A is Pathogenic according to our data. Variant chr9-36222885-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 553974.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-36222885-G-A is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GNE	NM_001128227.3	c.1618C>T	p.His540Tyr	missense_variant	9/12	ENST00000396594.8
GNE	NM_005476.7	c.1525C>T	p.His509Tyr	missense_variant	9/12	ENST00000642385.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GNE	ENST00000396594.8	c.1618C>T	p.His540Tyr	missense_variant	9/12	1	NM_001128227.3
GNE	ENST00000642385.2	c.1525C>T	p.His509Tyr	missense_variant	9/12		NM_005476.7	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000795 AC: 2 AN: 251490 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 135922

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000109

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000274 AC: 4 AN: 1461810 Hom.: 0 Cov.: 33 AF XY: 0.00000138 AC XY: 1 AN XY: 727214

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000756

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000756

ExAC AF: 0.0000165 AC: 2

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

GNE myopathy Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	Counsyl	Oct 06, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Jan 23, 2024	- -

Sialuria;C1853926:GNE myopathy Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Invitae

Nov 14, 2023

This sequence change replaces histidine, which is basic and polar, with tyrosine, which is neutral and polar, at codon 540 of the GNE protein (p.His540Tyr). This variant is present in population databases (rs754892377, gnomAD 0.006%). This missense change has been observed in individuals with autosomal recessive GNE-related myopathy (PMID: 21307865, 22196754, 25986339). This variant is also known as c.1525C >T (p.H509Y). ClinVar contains an entry for this variant (Variation ID: 553974). 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. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.21
BayesDel_addAF	Uncertain	0.12	D
BayesDel_noAF	Uncertain	0.11
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.85	D;.;D;.;.;D
Eigen	Uncertain	0.47
Eigen_PC	Uncertain	0.56
FATHMM_MKL	Pathogenic	0.99	D
M_CAP	Uncertain	0.19	D
MetaRNN	Uncertain	0.57	D;D;D;D;D;D
MetaSVM	Pathogenic	0.91	D
MutationAssessor	Benign	1.3	L;.;L;.;.;L
MutationTaster	Benign	1.0	D;D;D;D;D;D
PrimateAI	Uncertain	0.65	T
Polyphen		0.78	P;P;P;.;.;P
Vest4		0.75, 0.80, 0.70, 0.67, 0.80
MutPred		0.50		Gain of phosphorylation at H509 (P = 0.032);.;Gain of phosphorylation at H509 (P = 0.032);.;.;Gain of phosphorylation at H509 (P = 0.032);
MVP		0.99
MPC		1.2
ClinPred		0.61	D
GERP RS		5.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.76
gMVP		0.83

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.20		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.20		Position offset: -19

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

Publications

LitVar

Other links and lift over

dbSNP: rs754892377; hg19: chr9-36222882;