chr9-36227261-A-C

Variant names:

• chr9-36227261-A-C
• rs1313840587
• NM_001128227.3:c.1361T>G

Variant summary

Our verdict is Likely pathogenic. The variant received 7 ACMG points: 7P and 0B. PM2 PP2 PP3_Strong

The NM_001128227.3(GNE):​c.1361T>G​(p.Ile454Arg) 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 Uncertain significance (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I454V) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 31)
• Consequence: GNE NM_001128227.3 missense
• Clinical Significance: Uncertain significance no assertion criteria provided U:1
• Conservation: PhyloP100: 8.53
• 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: Likely_pathogenic. The variant received 7 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: 4.032 (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, 0.98

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GNE	NM_001128227.3	c.1361T>G	p.Ile454Arg	missense_variant	Exon 7 of 12	ENST00000396594.8	NP_001121699.1
GNE	NM_005476.7	c.1268T>G	p.Ile423Arg	missense_variant	Exon 7 of 12	ENST00000642385.2	NP_005467.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GNE	ENST00000396594.8	c.1361T>G	p.Ile454Arg	missense_variant	Exon 7 of 12	1	NM_001128227.3	ENSP00000379839.3
GNE	ENST00000642385.2	c.1268T>G	p.Ile423Arg	missense_variant	Exon 7 of 12		NM_005476.7	ENSP00000494141.2

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 31

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: no assertion criteria provided

Submissions by phenotype

GNE myopathy Uncertain:1

Dec 29, 2017

Counsyl

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

This submission and the accompanying classification are no longer maintained by the submitter. For more information on current observations and classification, please contact variantquestions@myriad.com. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.97
BayesDel_addAF	Pathogenic	0.54	D
BayesDel_noAF	Pathogenic	0.54
CADD	Pathogenic	27
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.86	D;.;D;.;.;.;D
Eigen	Pathogenic	0.76
Eigen_PC	Pathogenic	0.78
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.96	.;D;D;D;D;D;.
M_CAP	Pathogenic	0.91	D
MetaRNN	Pathogenic	0.98	D;D;D;D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Benign	1.8	L;.;L;.;.;L;L
PhyloP100		8.5
PrimateAI	Pathogenic	0.84	D
PROVEAN	Benign	-1.1	.;N;N;N;D;N;N
REVEL	Pathogenic	0.95
Sift	Pathogenic	0.0	.;D;D;D;D;D;D
Sift4G	Uncertain	0.0040	.;D;D;D;D;D;D
Polyphen		1.0	D;D;D;.;.;.;D
Vest4		0.96, 0.96, 0.93, 0.93, 0.79
MutPred		0.93		Gain of methylation at I423 (P = 0.0078);.;Gain of methylation at I423 (P = 0.0078);.;.;Gain of methylation at I423 (P = 0.0078);Gain of methylation at I423 (P = 0.0078);
MVP		1.0
MPC		1.9
ClinPred		0.96	D
GERP RS		6.0
Varity_R		0.89
gMVP		0.98
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: rs1313840587; hg19: chr9-36227258;