rs764657091

Positions:

• chr9-36249400-G-A

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_001128227.3(GNE):​c.52-3C>T variant causes a splice region, splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000694 in 1,440,272 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 2/2 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: GNE NM_001128227.3 splice_region, splice_polypyrimidine_tract, intron
• Scores: Splicing: ADA: 0.0004801
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.0850

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_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.76).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GNE	NM_001128227.3	c.52-3C>T		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		ENST00000396594.8
GNE	NM_005476.7	c.-42-3C>T		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		ENST00000642385.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GNE	ENST00000396594.8	c.52-3C>T		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		1	NM_001128227.3
GNE	ENST00000642385.2	c.-42-3C>T		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant			NM_005476.7	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000408 AC: 1 AN: 244878 Hom.: 0 AF XY: 0.00000754 AC XY: 1 AN XY: 132648

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000300

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: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 6.94e-7 AC: 1 AN: 1440272 Hom.: 0 Cov.: 28 AF XY: 0.00000140 AC XY: 1 AN XY: 715930

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000230

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: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Sialuria;C1853926:GNE myopathy Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Nov 14, 2023

This sequence change falls in intron 1 of the GNE gene. It does not directly change the encoded amino acid sequence of the GNE protein. It affects a nucleotide within the consensus splice site. This variant is present in population databases (rs764657091, gnomAD 0.003%). This variant has not been reported in the literature in individuals affected with GNE-related conditions. ClinVar contains an entry for this variant (Variation ID: 569623). Variants that disrupt 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 is not likely to affect RNA splicing. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.76
CADD	Benign	5.9
DANN	Benign	0.77

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00048
dbscSNV1_RF	Benign	0.13

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

Publications

LitVar

Other links and lift over

dbSNP: rs764657091; hg19: chr9-36249397;