rs199877522

Variant names:

• chr9-36227397-C-A
• rs199877522
• NM_001128227.3:c.1225G>T

Your query was ambiguous. Multiple possible variants found:

• chr9-36227397-C-A
• chr9-36227397-C-G
• chr9-36227397-C-T

Variant summary

Our verdict is Pathogenic. The variant received 15 ACMG points: 15P and 0B. PS3 PM5 PP2 PP5_Very_Strong

The NM_005476.7(GNE):​c.1132G>T​(p.Asp378Tyr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000375 in 1,612,536 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★). ClinVar reports functional evidence for this variant: "SCV000565045: Published functional studies demonstrate a damaging effect (60% reduction in epimerase activity and 50% reduction in kinase activity as compared to wild type) (Penner et al., 2006)" and additional evidence is available in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D378E) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00020 (0 hom., cov: 31)
  • Exomes 𝑓: 0.00039 (0 hom.)
• Consequence: GNE NM_005476.7 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:11 O:2
• Conservation: PhyloP100: 2.90
• Publications: 19 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 15 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV000565045: Published functional studies demonstrate a damaging effect (60% reduction in epimerase activity and 50% reduction in kinase activity as compared to wild type) (Penner et al., 2006); SCV000712454: "In vitro functional studies support an impact to protein function (Noguchi 2004, Penner 2006)."; SCV000915287: In vitro studies showed that p.Asp378Tyr variant was associated with 60% reduction of epimerase and a 50% reduction of kinase activity compared to wild type (Penner et al., 2006).; SCV004813787: This variant results in reduced enzyme activity (Noguchi_2004).; SCV000836816: Experimental studies have shown that this missense change affects GNE function (PMID: 14707127, 16503651).
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr9-36227397-C-G is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 1324492.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• 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 GNE myopathy, sialuria, macrothrombocytopenia, isolated, congenital myopathy, platelet-type bleeding disorder 19.
• PP5: Variant 9-36227397-C-A is Pathogenic according to our data. Variant chr9-36227397-C-A is described in ClinVar as Pathogenic. ClinVar VariationId is 283278.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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.1225G>T	p.Asp409Tyr	missense	Exon 7 of 12	NP_001121699.1	Q9Y223-2
	GNE	NM_005476.7	MANE Select	c.1132G>T	p.Asp378Tyr	missense	Exon 7 of 12	NP_005467.1	Q9Y223-1
	GNE	NM_001374797.1		c.979G>T	p.Asp327Tyr	missense	Exon 6 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.1225G>T	p.Asp409Tyr	missense	Exon 7 of 12	ENSP00000379839.3	Q9Y223-2
	GNE	ENST00000642385.2	MANE Select	c.1132G>T	p.Asp378Tyr	missense	Exon 7 of 12	ENSP00000494141.2	Q9Y223-1
	GNE	ENST00000543356.7	TSL:1	c.955G>T	p.Asp319Tyr	missense	Exon 6 of 11	ENSP00000437765.3	A0A7I2SU25

Frequencies

GnomAD3 genomes AF: 0.000204 AC: 31 AN: 152106 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.0000724

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000656

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: 0.000368

Gnomad OTH AF: 0.000960

GnomAD2 exomes AF: 0.000159 AC: 40 AN: 251400 AF XY: 0.000184

Gnomad AFR exome AF: 0.0000616

Gnomad AMR exome AF: 0.00

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: 0.00

GnomAD4 exome AF: 0.000393 AC: 574 AN: 1460430 Hom.: 0 Cov.: 30 AF XY: 0.000356 AC XY: 259 AN XY: 726622

African (AFR) AF: 0.000120 AC: 4 AN: 33456

American (AMR) AF: 0.00 AC: 0 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26128

East Asian (EAS) AF: 0.00 AC: 0 AN: 39680

South Asian (SAS) AF: 0.00 AC: 0 AN: 86230

European-Finnish (FIN) AF: 0.0000749 AC: 4 AN: 53414

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5760

European-Non Finnish (NFE) AF: 0.000475 AC: 528 AN: 1110692

Other (OTH) AF: 0.000630 AC: 38 AN: 60348

GnomAD4 genome AF: 0.000204 AC: 31 AN: 152106 Hom.: 0 Cov.: 31 AF XY: 0.000148 AC XY: 11 AN XY: 74302

African (AFR) AF: 0.0000724 AC: 3 AN: 41438

American (AMR) AF: 0.0000656 AC: 1 AN: 15254

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

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: 0.000368 AC: 25 AN: 68018

Other (OTH) AF: 0.000960 AC: 2 AN: 2084

Alfa AF: 0.000210 Hom.: 0

Bravo AF: 0.000223

TwinsUK AF: 0.000539 AC: 2

ALSPAC AF: 0.000519 AC: 2

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.000115 AC: 14

EpiCase AF: 0.000382

EpiControl AF: 0.000237

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
5	-	-	GNE myopathy (6)
3	-	-	not provided (3)
1	-	-	Inborn genetic diseases (1)
1	-	-	Sialuria;C1853926:GNE myopathy (2)
1	-	-	Sialuria;C1853926:GNE myopathy;C5935593:Thrombocytopenia 12 with or without myopathy (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.24
BayesDel_addAF	Pathogenic	0.29	D
BayesDel_noAF	Pathogenic	0.49
CADD	Pathogenic	29
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.83	D
Eigen	Uncertain	0.58
Eigen_PC	Uncertain	0.64
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.97	D
M_CAP	Pathogenic	0.54	D
MetaRNN	Uncertain	0.67	D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Benign	0.81	L
PhyloP100		2.9
PrimateAI	Uncertain	0.75	T
PROVEAN	Uncertain	-3.9	D
REVEL	Pathogenic	0.80
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.0060	D
Polyphen		1.0	D
Vest4		0.87
MVP		0.99
MPC		1.6
ClinPred		0.43	T
GERP RS		6.0
Varity_R		0.90
gMVP		0.84
Mutation Taster		=6/94	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.16		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: rs199877522; hg19: chr9-36227394; COSMIC: COSV64951187;