rs745517517

Variant names:

• chr9-36246472-G-A
• rs745517517
• ENST00000543356.7:c.-3C>T

Your query was ambiguous. Multiple possible variants found:

• chr9-36246472-G-A
• chr9-36246472-G-T

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PP3_Strong PP5_Very_Strong

The NM_001190388.2(GNE):​c.-3C>T variant causes a 5 prime UTR premature start codon gain change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000011 in 1,458,630 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 Pathogenic (★★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000011 (0 hom.)
• Consequence: GNE NM_001190388.2 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:8
• Conservation: PhyloP100: 7.26
• Publications: 6 publications found

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

Our verdict: Pathogenic. The variant received 12 ACMG points.

• PP3: BayesDel_addAF computational evidence supports a deleterious effect, 0.514
• PP5: Variant 9-36246472-G-A is Pathogenic according to our data. Variant chr9-36246472-G-A is described in ClinVar as Pathogenic. ClinVar VariationId is 285936.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001190388.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GNE	NM_001128227.3	MANE Plus Clinical	c.268C>T	p.Arg90*	stop_gained	Exon 3 of 12	NP_001121699.1
	GNE	NM_005476.7	MANE Select	c.175C>T	p.Arg59*	stop_gained	Exon 3 of 12	NP_005467.1
	GNE	NM_001190388.2		c.-3C>T		5_prime_UTR_premature_start_codon_gain	Exon 2 of 11	NP_001177317.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GNE	ENST00000543356.7	TSL:1	c.-3C>T		5_prime_UTR_premature_start_codon_gain	Exon 2 of 11	ENSP00000437765.3
	GNE	ENST00000396594.8	TSL:1 MANE Plus Clinical	c.268C>T	p.Arg90*	stop_gained	Exon 3 of 12	ENSP00000379839.3
	GNE	ENST00000642385.2	MANE Select	c.175C>T	p.Arg59*	stop_gained	Exon 3 of 12	ENSP00000494141.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.0000283 AC: 7 AN: 247576 AF XY: 0.0000297

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000290

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000540

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000110 AC: 16 AN: 1458630 Hom.: 0 Cov.: 31 AF XY: 0.0000124 AC XY: 9 AN XY: 725794

African (AFR) AF: 0.00 AC: 0 AN: 33436

American (AMR) AF: 0.0000224 AC: 1 AN: 44714

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26120

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86174

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53146

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5468

European-Non Finnish (NFE) AF: 0.0000117 AC: 13 AN: 1109574

Other (OTH) AF: 0.0000166 AC: 1 AN: 60300

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000658 Hom.: 0

Bravo AF: 0.0000151

ExAC AF: 0.0000413 AC: 5

ClinVar

ClinVar submissions as Germline

Significance: Pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
4	-	-	GNE myopathy (4)
2	-	-	not provided (2)
1	-	-	Sialuria;C1853926:GNE myopathy (1)
1	-	-	Sialuria;C1853926:GNE myopathy;C5935593:Thrombocytopenia 12 with or without myopathy (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.51	D
BayesDel_noAF	Pathogenic	0.55
CADD	Pathogenic	38
DANN	Uncertain	0.98
Eigen	Uncertain	0.24
Eigen_PC	Benign	0.068
FATHMM_MKL	Pathogenic	0.99	D
PhyloP100		7.3
Vest4		0.84
GERP RS		4.3
Mutation Taster		=0/200	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
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

Other links and lift over

dbSNP: rs745517517; hg19: chr9-36246469; COSMIC: COSV100929845;