9-36227253-T-G

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 3P and 2B. PM2PP2BP4_Moderate

The NM_001128227.3(GNE):c.1369A>C(p.Met457Leu) variant causes a missense change. The variant allele was found at a frequency of 0.00000187 in 1,606,496 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. M457T) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 32)

Exomes 𝑓: 6.9e-7 ( 0 hom. )

Consequence

GNE
NM_001128227.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:3

Conservation

PhyloP100: 5.53

Publications

1 publications found

Variant links:

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]

GNE links:

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]

CLTA links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 1 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.

BP4

Computational evidence support a benign effect (MetaRNN=0.13395968).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001128227.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
GNE	NM_001128227.3	MANE Plus Clinical	c.1369A>C	p.Met457Leu	missense	Exon 7 of 12	NP_001121699.1
GNE	NM_005476.7	MANE Select	c.1276A>C	p.Met426Leu	missense	Exon 7 of 12	NP_005467.1
GNE	NM_001374797.1		c.1123A>C	p.Met375Leu	missense	Exon 6 of 11	NP_001361726.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
GNE	ENST00000396594.8	TSL:1 MANE Plus Clinical	c.1369A>C	p.Met457Leu	missense	Exon 7 of 12	ENSP00000379839.3
GNE	ENST00000642385.2	MANE Select	c.1276A>C	p.Met426Leu	missense	Exon 7 of 12	ENSP00000494141.2
GNE	ENST00000543356.7	TSL:1	c.1099A>C	p.Met367Leu	missense	Exon 6 of 11	ENSP00000437765.3

Frequencies

GnomAD3 genomes

AF:

0.0000131

AC:

AN:

152182

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000385

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000199

AC:

AN:

251442

AF XY:

0.00000736

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000272

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

6.88e-7

AC:

AN:

1454314

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

723978

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33300

American (AMR)

AF:

0.00

AC:

AN:

44720

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26084

East Asian (EAS)

AF:

0.0000252

AC:

AN:

39664

South Asian (SAS)

AF:

0.00

AC:

AN:

86078

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53416

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5750

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1105188

Other (OTH)

AF:

0.00

AC:

AN:

60114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0000131

AC:

AN:

152182

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74338

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41450

American (AMR)

AF:

0.00

AC:

AN:

15274

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.000385

AC:

AN:

5200

South Asian (SAS)

AF:

0.00

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10616

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

68026

Other (OTH)

AF:

0.00

AC:

AN:

2088

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000756

ExAC

AF:

0.0000330

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Inborn genetic diseases

Uncertain:1

Mar 20, 2024

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.1369A>C (p.M457L) alteration is located in exon 7 (coding exon 7) of the GNE gene. This alteration results from a A to C substitution at nucleotide position 1369, causing the methionine (M) at amino acid position 457 to be replaced by a leucine (L). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.

Sialuria;C1853926:GNE myopathy

Uncertain:1

Oct 24, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces methionine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 457 of the GNE protein (p.Met457Leu). This variant is present in population databases (rs750404513, gnomAD 0.04%). This variant has not been reported in the literature in individuals affected with GNE-related conditions. ClinVar contains an entry for this variant (Variation ID: 284972). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed for this missense variant. However, the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on GNE protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

not provided

Uncertain:1

Dec 11, 2015

Eurofins Ntd Llc (ga)

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.16

BayesDel_addAF

Benign

-0.0068

BayesDel_noAF

Uncertain

0.050

CADD

Benign

(source)

DANN

Benign

0.97

DEOGEN2

Uncertain

0.68

Eigen

Benign

-0.52

Eigen_PC

Benign

-0.20

FATHMM_MKL

Uncertain

0.97

LIST_S2

Uncertain

0.96

M_CAP

Uncertain

0.21

MetaRNN

Benign

0.13

MetaSVM

Uncertain

0.26

MutationAssessor

Benign

-1.4

PhyloP100

5.5

PrimateAI

Uncertain

0.79

PROVEAN

Benign

-0.47

REVEL

Uncertain

0.46

Sift

Benign

0.051

Sift4G

Benign

0.29

Polyphen

0.042

Vest4

0.52

MutPred

0.61

Loss of MoRF binding (P = 0.0873)

MVP

0.72

MPC

0.55

ClinPred

0.19

GERP RS

3.5

Varity_R

0.43

gMVP

0.65

Mutation Taster

=43/57

disease causing

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over