rs141814943

Variant names:

• chr9-36234098-C-T
• rs141814943
• NM_001128227.3:c.897G>A

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Moderate BP6 BP7

The NM_001128227.3(GNE):​c.897G>A​(p.Lys299Lys) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000292 in 1,613,788 control chromosomes in the GnomAD database, including 1 homozygotes. 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: 𝑓 0.00014 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00031 (1 hom.)
• Consequence: GNE NM_001128227.3 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:5
• Conservation: PhyloP100: 1.03
• Publications: 1 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: Likely_benign. The variant received -4 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.32).
• BP6: Variant 9-36234098-C-T is Benign according to our data. Variant chr9-36234098-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 285652.
• BP7: Synonymous conserved (PhyloP=1.03 with no splicing effect.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001128227.3. 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.897G>A	p.Lys299Lys	synonymous	Exon 5 of 12	NP_001121699.1
	GNE	NM_005476.7	MANE Select	c.804G>A	p.Lys268Lys	synonymous	Exon 5 of 12	NP_005467.1
	GNE	NM_001374797.1		c.651G>A	p.Lys217Lys	synonymous	Exon 4 of 11	NP_001361726.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GNE	ENST00000396594.8	TSL:1 MANE Plus Clinical	c.897G>A	p.Lys299Lys	synonymous	Exon 5 of 12	ENSP00000379839.3
	GNE	ENST00000642385.2	MANE Select	c.804G>A	p.Lys268Lys	synonymous	Exon 5 of 12	ENSP00000494141.2
	GNE	ENST00000543356.7	TSL:1	c.627G>A	p.Lys209Lys	synonymous	Exon 4 of 11	ENSP00000437765.3

Frequencies

GnomAD3 genomes AF: 0.000145 AC: 22 AN: 152158 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000483

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000265

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000179 AC: 45 AN: 251478 AF XY: 0.000206

Gnomad AFR exome AF: 0.0000615

Gnomad AMR exome AF: 0.000116

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000343

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.000307 AC: 449 AN: 1461630 Hom.: 1 Cov.: 31 AF XY: 0.000323 AC XY: 235 AN XY: 727138

African (AFR) AF: 0.0000896 AC: 3 AN: 33478

American (AMR) AF: 0.000112 AC: 5 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26130

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86244

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.000384 AC: 427 AN: 1111786

Other (OTH) AF: 0.000232 AC: 14 AN: 60384

GnomAD4 genome AF: 0.000145 AC: 22 AN: 152158 Hom.: 0 Cov.: 32 AF XY: 0.0000942 AC XY: 7 AN XY: 74324

African (AFR) AF: 0.0000483 AC: 2 AN: 41434

American (AMR) AF: 0.000131 AC: 2 AN: 15268

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5192

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10608

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.000265 AC: 18 AN: 68038

Other (OTH) AF: 0.00 AC: 0 AN: 2094

Alfa AF: 0.000201 Hom.: 0

Bravo AF: 0.000200

EpiCase AF: 0.000491

EpiControl AF: 0.000652

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	2	not provided (3)
-	-	1	GNE myopathy (1)
-	-	1	GNE-related disorder (1)
-	-	1	Sialuria;C1853926:GNE myopathy (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.32
CADD	Benign	11
DANN	Benign	0.82
PhyloP100		1.0

Splicing

Name	Calibrated prediction	Score	Prediction
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

Other links and lift over

dbSNP: rs141814943; hg19: chr9-36234095;