rs886063926

chr9-36236828-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3 PP5

The NM_001128227.3(GNE):c.862+4A>G variant causes a splice donor region, intron change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency: Genomes: not found (cov: 32)
• Consequence: GNE NM_001128227.3 splice_donor_region, intron
• Scores: Splicing: ADA: 0.9930
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:2
• Conservation: PhyloP100: 3.39

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 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• 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 9-36236828-T-C is Pathogenic according to our data. Variant chr9-36236828-T-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 366844.We mark this variant Likely_pathogenic, oryginal submissions are: {Pathogenic=1, Uncertain_significance=2}. Variant chr9-36236828-T-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GNE	NM_001128227.3	c.862+4A>G		splice_donor_region_variant, intron_variant		ENST00000396594.8
GNE	NM_005476.7	c.769+4A>G		splice_donor_region_variant, intron_variant		ENST00000642385.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GNE	ENST00000396594.8	c.862+4A>G		splice_donor_region_variant, intron_variant		1	NM_001128227.3
GNE	ENST00000642385.2	c.769+4A>G		splice_donor_region_variant, intron_variant			NM_005476.7	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1 Uncertain:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Sialuria;C1853926:GNE myopathy Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Jun 06, 2023

This variant has been observed in individuals with clinical features of autosomal recessive distal myopathy (PMID: 12473753, 24027297; Invitae). This variant is not present in population databases (gnomAD no frequency). This sequence change falls in intron 4 of the GNE gene. It does not directly change the encoded amino acid sequence of the GNE protein. RNA analysis indicates that this variant induces altered splicing and may result in an absent or disrupted protein product. This variant is also known as IVS4+4A>G and c.769+4A>G. For these reasons, this variant has been classified as Pathogenic. Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Studies have shown that this variant results in skipping of exon 4 and introduces a premature termination codon (PMID: 12473753). The resulting mRNA is expected to undergo nonsense-mediated decay. ClinVar contains an entry for this variant (Variation ID: 366844). -

Sialuria Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 2017

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -

GNE myopathy Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 2017

The GNE c.769+4A>G variant is a splice region variant that has been found in a compound heterozygous state in at least two individuals with GNE-related myopathy (Nishino et al. 2002; Fischer et al. 2013). Control data are unavailable for this variant, which is not found in the 1000 Genomes Project, Exome Sequencing Project or Exome Aggregation Consortium despite being located in a region of good sequencing coverage. The variant is thus presumed to be rare. Nishino et al. (2002) reported that the c.769+4A>G variant resulted in virtually complete skipping of exon 4 when cDNA was analyzed. The evidence for this variant is limited. The c.769+4A>G variant is thus classified as a variant of unknown significance but suspicious for pathogenicity for GNE-related myopathy. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.32
Cadd	Uncertain	25
Dann	Benign	0.97

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	0.99
dbscSNV1_RF	Pathogenic	0.88
SpliceAI score (max)		0.020		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: rs886063926; hg19: chr9-36236825;