rs1447770049

Variant names:

• chr9-36223483-T-C
• rs1447770049
• NM_001128227.3:c.1394A>G

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PP2 PP3

The NM_005476.7(GNE):​c.1301A>G​(p.Tyr434Cys) variant causes a missense change. The variant allele was found at a frequency of 0.000000686 in 1,458,764 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 Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. Y434Y) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: GNE NM_005476.7 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:2
• Conservation: PhyloP100: 4.22
• Publications: 3 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: Uncertain_significance. The variant received 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in the GNE gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 44 curated pathogenic missense variants (we use a threshold of 10). The gene has 1 curated benign missense variants. Gene score misZ: 2.5904 (below the threshold of 3.09). Trascript score misZ: 3.9915 (above the threshold of 3.09). GenCC associations: The gene is linked to sialuria, GNE myopathy, congenital myopathy, platelet-type bleeding disorder 19, macrothrombocytopenia, isolated.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.766

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005476.7. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GNE	NM_001128227.3	MANE Plus Clinical	c.1394A>G	p.Tyr465Cys	missense	Exon 8 of 12	NP_001121699.1
	GNE	NM_005476.7	MANE Select	c.1301A>G	p.Tyr434Cys	missense	Exon 8 of 12	NP_005467.1
	GNE	NM_001374797.1		c.1148A>G	p.Tyr383Cys	missense	Exon 7 of 11	NP_001361726.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GNE	ENST00000396594.8	TSL:1 MANE Plus Clinical	c.1394A>G	p.Tyr465Cys	missense	Exon 8 of 12	ENSP00000379839.3
	GNE	ENST00000642385.2	MANE Select	c.1301A>G	p.Tyr434Cys	missense	Exon 8 of 12	ENSP00000494141.2
	GNE	ENST00000543356.7	TSL:1	c.1124A>G	p.Tyr375Cys	missense	Exon 7 of 11	ENSP00000437765.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000398 AC: 1 AN: 251284 AF XY: 0.00

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 FIN exome AF: 0.0000462

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 6.86e-7 AC: 1 AN: 1458764 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 725914

African (AFR) AF: 0.00 AC: 0 AN: 33418

American (AMR) AF: 0.00 AC: 0 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26118

East Asian (EAS) AF: 0.00 AC: 0 AN: 39688

South Asian (SAS) AF: 0.00 AC: 0 AN: 86192

European-Finnish (FIN) AF: 0.0000187 AC: 1 AN: 53402

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5120

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1109870

Other (OTH) AF: 0.00 AC: 0 AN: 60236

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	GNE myopathy (1)
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.22
BayesDel_addAF	Pathogenic	0.48	D
BayesDel_noAF	Pathogenic	0.45
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.81	D
Eigen	Uncertain	0.34
Eigen_PC	Uncertain	0.44
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.95	D
M_CAP	Pathogenic	0.72	D
MetaRNN	Pathogenic	0.77	D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Benign	0.90	L
PhyloP100		4.2
PrimateAI	Pathogenic	0.88	D
PROVEAN	Benign	-0.95	N
REVEL	Pathogenic	0.72
Sift	Uncertain	0.0090	D
Sift4G	Benign	0.15	T
Polyphen		0.82	P
Vest4		0.47
MutPred		0.49		Gain of methylation at K433 (P = 0.0157)
MVP		0.97
MPC		0.67
ClinPred		0.53	D
GERP RS		5.7
Varity_R		0.71
gMVP		0.78
Mutation Taster		=0/100	disease causing

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: rs1447770049; hg19: chr9-36223480;