chr9-36227397-C-G

Variant names:

• chr9-36227397-C-G
• rs199877522
• NM_001128227.3:c.1225G>C

Variant summary

Our verdict is Pathogenic. The variant received 13 ACMG points: 13P and 0B. PM2 PM5 PP2 PP5_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
• Clinical Significance: Likely pathogenic criteria provided, multiple submitters, no conflicts P:2
• Conservation: PhyloP100: 2.90
• Publications: 18 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: 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
GNE	NM_001128227.3	c.1225G>C	p.Asp409His	missense_variant	Exon 7 of 12	ENST00000396594.8	NP_001121699.1
GNE	NM_005476.7	c.1132G>C	p.Asp378His	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.1225G>C	p.Asp409His	missense_variant	Exon 7 of 12	1	NM_001128227.3	ENSP00000379839.3
GNE	ENST00000642385.2	c.1132G>C	p.Asp378His	missense_variant	Exon 7 of 12		NM_005476.7	ENSP00000494141.2

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

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

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

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

Other links and lift over

dbSNP: rs199877522; hg19: chr9-36227394;