9-36227253-T-G

Variant names:

• chr9-36227253-T-G
• rs750404513
• NM_001128227.3:c.1369A>C

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 3P and 2B. PM2 PP2 BP4_Moderate

The NM_005476.7(GNE):​c.1276A>C​(p.Met426Leu) 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. M426T) 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_005476.7 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:3
• Conservation: PhyloP100: 5.53
• Publications: 1 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: 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: 3.9915 (above the threshold of 3.09). GenCC associations: The gene is linked to GNE myopathy, sialuria, macrothrombocytopenia, isolated, congenital myopathy, platelet-type bleeding disorder 19.
• BP4: Computational evidence support a benign effect (MetaRNN=0.13395968).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005476.7. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GNE	NM_001128227.3	MANE Plus Clinical	c.1369A>C	p.Met457Leu	missense	Exon 7 of 12	NP_001121699.1	Q9Y223-2
	GNE	NM_005476.7	MANE Select	c.1276A>C	p.Met426Leu	missense	Exon 7 of 12	NP_005467.1	Q9Y223-1
	GNE	NM_001374797.1		c.1123A>C	p.Met375Leu	missense	Exon 6 of 11	NP_001361726.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GNE	ENST00000396594.8	TSL:1 MANE Plus Clinical	c.1369A>C	p.Met457Leu	missense	Exon 7 of 12	ENSP00000379839.3	Q9Y223-2
	GNE	ENST00000642385.2	MANE Select	c.1276A>C	p.Met426Leu	missense	Exon 7 of 12	ENSP00000494141.2	Q9Y223-1
	GNE	ENST00000543356.7	TSL:1	c.1099A>C	p.Met367Leu	missense	Exon 6 of 11	ENSP00000437765.3	A0A7I2SU25

Frequencies

GnomAD3 genomes AF: 0.0000131 AC: 2 AN: 152182 Hom.: 0 Cov.: 32

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: 5 AN: 251442 AF XY: 0.00000736

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: 1 AN: 1454314 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 723978

African (AFR) AF: 0.00 AC: 0 AN: 33300

American (AMR) AF: 0.00 AC: 0 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26084

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39664

South Asian (SAS) AF: 0.00 AC: 0 AN: 86078

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53416

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5750

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1105188

Other (OTH) AF: 0.00 AC: 0 AN: 60114

GnomAD4 genome AF: 0.0000131 AC: 2 AN: 152182 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74338

African (AFR) AF: 0.00 AC: 0 AN: 41450

American (AMR) AF: 0.00 AC: 0 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.000385 AC: 2 AN: 5200

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10616

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68026

Other (OTH) AF: 0.00 AC: 0 AN: 2088

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000756

ExAC AF: 0.0000330 AC: 4

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	1	-	Inborn genetic diseases (1)
-	1	-	not provided (1)
-	1	-	Sialuria;C1853926:GNE myopathy (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Benign	-0.0068	T
BayesDel_noAF	Uncertain	0.050
CADD	Benign	21
DANN	Benign	0.97
DEOGEN2	Uncertain	0.68	D
Eigen	Benign	-0.52
Eigen_PC	Benign	-0.20
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Uncertain	0.96	D
M_CAP	Uncertain	0.21	D
MetaRNN	Benign	0.13	T
MetaSVM	Uncertain	0.26	D
MutationAssessor	Benign	-1.4	N
PhyloP100		5.5
PrimateAI	Uncertain	0.79	T
PROVEAN	Benign	-0.47	N
REVEL	Uncertain	0.46
Sift	Benign	0.051	T
Sift4G	Benign	0.29	T
Polyphen		0.042	B
Vest4		0.52
MutPred		0.61		Loss of MoRF binding (P = 0.0873)
MVP		0.72
MPC		0.55
ClinPred		0.19	T
GERP RS		3.5
Varity_R		0.43
gMVP		0.65
Mutation Taster		=43/57	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: rs750404513; hg19: chr9-36227250;