chr9-36227397-C-G

Variant summary

Our verdict is Pathogenic. The variant received 13 ACMG points: 13P and 0B. PM2PM5PP2PP5_Very_Strong

The NM_001128227.3(GNE):​c.1225G>C​(p.Asp409His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,460,436 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. D409E) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 31)
Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

GNE
NM_001128227.3 missense

Scores

5
11
3

Clinical Significance

Likely pathogenic criteria provided, multiple submitters, no conflicts P:2

Conservation

PhyloP100: 2.90

Publications

18 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]
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]

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 13 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PM5
Other missense variant is known to change same aminoacid residue: Variant chr9-36227397-C-A is described in CliVar as Pathogenic. Clinvar id is 283278.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: 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.
PP5
Variant 9-36227397-C-G is Pathogenic according to our data. Variant chr9-36227397-C-G is described in CliVar as Likely_pathogenic. Clinvar id is 1324492.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-36227397-C-G is described in CliVar as Likely_pathogenic. Clinvar id is 1324492.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-36227397-C-G is described in CliVar as Likely_pathogenic. Clinvar id is 1324492.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-36227397-C-G is described in CliVar as Likely_pathogenic. Clinvar id is 1324492.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-36227397-C-G is described in CliVar as Likely_pathogenic. Clinvar id is 1324492.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-36227397-C-G is described in CliVar as Likely_pathogenic. Clinvar id is 1324492.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-36227397-C-G is described in CliVar as Likely_pathogenic. Clinvar id is 1324492.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-36227397-C-G is described in CliVar as Likely_pathogenic. Clinvar id is 1324492.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-36227397-C-G is described in CliVar as Likely_pathogenic. Clinvar id is 1324492.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-36227397-C-G is described in CliVar as Likely_pathogenic. Clinvar id is 1324492.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-36227397-C-G is described in CliVar as Likely_pathogenic. Clinvar id is 1324492.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-36227397-C-G is described in CliVar as Likely_pathogenic. Clinvar id is 1324492.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-36227397-C-G is described in CliVar as Likely_pathogenic. Clinvar id is 1324492.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
GNENM_001128227.3 linkc.1225G>C p.Asp409His missense_variant Exon 7 of 12 ENST00000396594.8 NP_001121699.1 Q9Y223-2
GNENM_005476.7 linkc.1132G>C p.Asp378His missense_variant Exon 7 of 12 ENST00000642385.2 NP_005467.1 Q9Y223-1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
GNEENST00000396594.8 linkc.1225G>C p.Asp409His missense_variant Exon 7 of 12 1 NM_001128227.3 ENSP00000379839.3 Q9Y223-2
GNEENST00000642385.2 linkc.1132G>C p.Asp378His missense_variant Exon 7 of 12 NM_005476.7 ENSP00000494141.2 Q9Y223-1

Frequencies

GnomAD3 genomes
Cov.:
31
GnomAD4 exome
AF:
6.85e-7
AC:
1
AN:
1460436
Hom.:
0
Cov.:
30
AF XY:
0.00
AC XY:
0
AN XY:
726622
show subpopulations
African (AFR)
AF:
0.00
AC:
0
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:
0.0000116
AC:
1
AN:
86230
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
53414
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
5760
European-Non Finnish (NFE)
AF:
0.00
AC:
0
AN:
1110698
Other (OTH)
AF:
0.00
AC:
0
AN:
60348
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.425
Heterozygous variant carriers
0
0
1
1
2
2
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Exome Het
Variant carriers
0
2
4
6
8
10
<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
Cov.:
31
Alfa
AF:
0.00
Hom.:
0
Bravo
AF:
0.00000378

ClinVar

Significance: Likely pathogenic
Submissions summary: Pathogenic:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

GNE myopathy Pathogenic:1
Jul 10, 2024
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Significance:Likely pathogenic
Review Status:criteria provided, single submitter
Collection Method:clinical testing

Variant summary: GNE c.1225G>C (p.Asp409His) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251400 control chromosomes. c.1225G>C has been reported in the literature in at-least two individuals affected with Hereditary Muscle Disorders and GNE-related myopathy (Chen_2019, Khadilkar_2021,2022, Lv_2022). These data indicate that the variant may be associated with disease. A different variant affecting the same codon has been classified as pathogenic by our lab (c.1225G>T, p.Asp409Tyr), supporting the critical relevance of codon 409 to GNE protein function. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 30390020, 35723113, 33197058, 35138478). ClinVar contains an entry for this variant (Variation ID: 1324492). Based on the evidence outlined above, the variant was classified as likely pathogenic. -

not provided Pathogenic:1
Jul 25, 2019
Revvity Omics, Revvity
Significance:Likely pathogenic
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.19
BayesDel_addAF
Pathogenic
0.36
D
BayesDel_noAF
Pathogenic
0.28
CADD
Pathogenic
27
DANN
Uncertain
1.0
DEOGEN2
Uncertain
0.77
D;.;D;.;.;.;D
Eigen
Uncertain
0.57
Eigen_PC
Uncertain
0.63
FATHMM_MKL
Uncertain
0.96
D
LIST_S2
Uncertain
0.97
.;D;D;D;D;D;.
M_CAP
Pathogenic
0.60
D
MetaRNN
Uncertain
0.73
D;D;D;D;D;D;D
MetaSVM
Pathogenic
1.0
D
MutationAssessor
Benign
0.81
L;.;L;.;.;L;L
PhyloP100
2.9
PrimateAI
Uncertain
0.76
T
PROVEAN
Uncertain
-2.9
.;D;D;N;D;D;D
REVEL
Pathogenic
0.71
Sift
Uncertain
0.0050
.;D;D;D;D;D;D
Sift4G
Uncertain
0.017
.;D;D;D;D;D;D
Polyphen
1.0
D;D;D;.;.;.;D
Vest4
0.55, 0.54, 0.54, 0.53, 0.43, 0.54
MutPred
0.53
Loss of stability (P = 0.117);.;Loss of stability (P = 0.117);.;.;Loss of stability (P = 0.117);Loss of stability (P = 0.117);
MVP
0.99
MPC
1.5
ClinPred
0.97
D
GERP RS
6.0
Varity_R
0.58
gMVP
0.75
Mutation Taster
=4/96
disease causing

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.020
Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

Other links and lift over

dbSNP: rs199877522; hg19: chr9-36227394; API