rs766266918

Positions:

• chr9-36246031-C-T

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PP2 PP3_Moderate PP5

The NM_001128227.3(GNE):​c.709G>A​(p.Gly237Ser) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.00000137 in 1,459,618 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: GNE NM_001128227.3 missense, splice_region
• Scores: Splicing: ADA: 0.9998
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2 U:1
• Conservation: PhyloP100: 7.15

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 Likely_pathogenic. Variant got 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• 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: dbscSNV1_ADA, dbscSNV1_RF. No scorers claiming Uncertain. Scorers claiming Benign: max_spliceai.
• PP5: Variant 9-36246031-C-T is Pathogenic according to our data. Variant chr9-36246031-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 497177.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=2, Uncertain_significance=1}. Variant chr9-36246031-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.709G>A	p.Gly237Ser	missense_variant, splice_region_variant	3/12	ENST00000396594.8	NP_001121699.1
GNE	NM_005476.7	c.616G>A	p.Gly206Ser	missense_variant, splice_region_variant	3/12	ENST00000642385.2	NP_005467.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GNE	ENST00000396594.8	c.709G>A	p.Gly237Ser	missense_variant, splice_region_variant	3/12	1	NM_001128227.3	ENSP00000379839
GNE	ENST00000642385.2	c.616G>A	p.Gly206Ser	missense_variant, splice_region_variant	3/12		NM_005476.7	ENSP00000494141	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000398 AC: 1 AN: 251138 Hom.: 0 AF XY: 0.00000737 AC XY: 1 AN XY: 135766

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: 0.00000880

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1459618 Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1 AN XY: 726268

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: 0.00000180

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:2 Uncertain:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Sialuria;C1853926:GNE myopathy Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jun 16, 2021

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. Nucleotide substitutions within the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site, but this prediction has not been confirmed by published transcriptional studies. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C55"). This variant has been observed in individual(s) with autosomal recessive hereditary inclusion-body myopathy (PMID: 15146476). It has also been observed to segregate with disease in related individuals. It is also known as p.G206S in literature. ClinVar contains an entry for this variant (Variation ID: 497177). This variant is present in population databases (rs766266918, ExAC 0.001%). This sequence change replaces glycine with serine at codon 237 of the GNE protein (p.Gly237Ser). The glycine residue is highly conserved and there is a small physicochemical difference between glycine and serine. This variant also falls at the last nucleotide of exon 3 of the GNE coding sequence, which is part of the consensus splice site for this exon. -

GNE myopathy Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

Mar 19, 2024

- -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Eurofins Ntd Llc (ga)

Oct 19, 2016

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Pathogenic	0.45	D
BayesDel_noAF	Pathogenic	0.41
CADD	Uncertain	26
DANN	Uncertain	0.99
Eigen	Uncertain	0.61
Eigen_PC	Uncertain	0.56
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.53	T
M_CAP	Pathogenic	0.86	D
MetaRNN	Pathogenic	0.91	D
MetaSVM	Pathogenic	1.1	D
MutationTaster	Benign	1.0	D;D;D;D;D;D
PROVEAN	Uncertain	-3.2	D
REVEL	Pathogenic	0.80
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.029	D
Vest4		0.79
MutPred		0.60		Loss of sheet (P = 3e-04);
MVP		0.93
ClinPred		0.87	D
GERP RS		5.5

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.95
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: rs766266918; hg19: chr9-36246028;