rs121908634

Variant names:

• chr9-36246136-T-C
• rs121908634
• NM_001128227.3:c.604A>G

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM1 PM2 PP2 PP3_Strong PP5

The NM_005476.7(GNE):​c.511A>G​(p.Met171Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,852 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 (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. M171T) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: GNE NM_005476.7 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 7.25

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 Pathogenic. Variant got 10 ACMG points.

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 5 uncertain in NM_005476.7
• 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 macrothrombocytopenia, isolated, platelet-type bleeding disorder 19, sialuria, GNE myopathy.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.974
• PP5: Variant 9-36246136-T-C is Pathogenic according to our data. Variant chr9-36246136-T-C is described in ClinVar as [Pathogenic]. Clinvar id is 6036.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr9-36246136-T-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GNE	NM_001128227.3	c.604A>G	p.Met202Val	missense_variant	Exon 3 of 12	ENST00000396594.8	NP_001121699.1
GNE	NM_005476.7	c.511A>G	p.Met171Val	missense_variant	Exon 3 of 12	ENST00000642385.2	NP_005467.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GNE	ENST00000396594.8	c.604A>G	p.Met202Val	missense_variant	Exon 3 of 12	1	NM_001128227.3	ENSP00000379839.3
GNE	ENST00000642385.2	c.511A>G	p.Met171Val	missense_variant	Exon 3 of 12		NM_005476.7	ENSP00000494141.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461852 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 727236

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

GNE myopathy Pathogenic:1

Dec 10, 2002

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.71
BayesDel_addAF	Pathogenic	0.52	D
BayesDel_noAF	Pathogenic	0.51
CADD	Pathogenic	27
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.98	D;.;D;.;.;.;D
Eigen	Pathogenic	0.80
Eigen_PC	Pathogenic	0.77
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.96	.;D;D;D;D;D;.
M_CAP	Pathogenic	0.89	D
MetaRNN	Pathogenic	0.97	D;D;D;D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Uncertain	2.5	M;.;M;.;.;M;M
PrimateAI	Uncertain	0.78	T
PROVEAN	Uncertain	-2.5	.;D;D;.;N;D;D
REVEL	Pathogenic	0.94
Sift	Uncertain	0.0010	.;D;D;.;D;D;D
Sift4G	Uncertain	0.011	.;D;D;D;D;D;D
Polyphen		0.99	D;D;D;.;.;.;D
Vest4		0.82, 0.81, 0.79, 0.72, 0.69
MutPred		0.88		Gain of helix (P = 0.132);.;Gain of helix (P = 0.132);.;.;Gain of helix (P = 0.132);Gain of helix (P = 0.132);
MVP		0.99
MPC		1.5
ClinPred		0.95	D
GERP RS		5.7
Varity_R		0.89
gMVP		0.95

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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: rs121908634; hg19: chr9-36246133;