rs121908623

Positions:

• chr9-36234114-C-A

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PM2 PP2 PP3_Strong PP5_Moderate

The ENST00000396594.8(GNE):​c.881G>T​(p.Arg294Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R294Q) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: GNE ENST00000396594.8 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:2 O:1
• Conservation: PhyloP100: 7.22

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_pathogenic. Variant got 9 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), GNE. . Gene score misZ 2.5904 (greater than the threshold 3.09). Trascript score misZ 4.032 (greater than threshold 3.09). GenCC has associacion of gene with macrothrombocytopenia, isolated, platelet-type bleeding disorder 19, sialuria, GNE myopathy.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.976
• PP5: Variant 9-36234114-C-A is Pathogenic according to our data. Variant chr9-36234114-C-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 6023.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr9-36234114-C-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GNE	NM_001128227.3	c.881G>T	p.Arg294Leu	missense_variant	5/12	ENST00000396594.8	NP_001121699.1
GNE	NM_005476.7	c.788G>T	p.Arg263Leu	missense_variant	5/12	ENST00000642385.2	NP_005467.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GNE	ENST00000396594.8	c.881G>T	p.Arg294Leu	missense_variant	5/12	1	NM_001128227.3	ENSP00000379839
GNE	ENST00000642385.2	c.788G>T	p.Arg263Leu	missense_variant	5/12		NM_005476.7	ENSP00000494141	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:2 Other:1

Revision: criteria provided, single submitter

Submissions by phenotype

Sialuria Pathogenic:2 Other:1

not provided, no classification provided	literature only	GeneReviews	-	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Jun 01, 1999	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein	Jun 23, 2021	ACMG classification criteria: PS3 supporting, PS4 supporting, PM1 moderate, PM2 moderate, PP3 supporting -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.85
BayesDel_addAF	Pathogenic	0.53	D
BayesDel_noAF	Pathogenic	0.52
CADD	Pathogenic	33
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.94	D;.;D;.;.;.;D
Eigen	Pathogenic	0.83
Eigen_PC	Pathogenic	0.83
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.98	.;D;D;D;D;D;.
M_CAP	Pathogenic	0.94	D
MetaRNN	Pathogenic	0.98	D;D;D;D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Benign	1.5	L;.;L;.;.;L;L
MutationTaster	Benign	1.0	A;A;A;A;A;A
PrimateAI	Pathogenic	0.85	D
PROVEAN	Uncertain	-3.7	.;D;D;.;D;D;D
REVEL	Pathogenic	0.94
Sift	Uncertain	0.010	.;D;D;.;D;D;D
Sift4G	Uncertain	0.018	.;D;D;D;D;D;D
Polyphen		1.0	D;D;D;.;.;.;D
Vest4		0.92, 0.91, 0.90, 0.88, 0.91
MutPred		0.87		Loss of MoRF binding (P = 0.004);.;Loss of MoRF binding (P = 0.004);.;.;Loss of MoRF binding (P = 0.004);Loss of MoRF binding (P = 0.004);
MVP		0.99
MPC		1.6
ClinPred		1.0	D
GERP RS		5.8
Varity_R		0.96
gMVP		0.93

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

Publications

LitVar

Other links and lift over

dbSNP: rs121908623; hg19: chr9-36234111;