9-36227262-T-C

Variant names:

• chr9-36227262-T-C
• rs35638832
• NM_001128227.3:c.1360A>G

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 1P and 9B. PP2 BP4_Strong BP6 BS1

The NM_005476.7(GNE):​c.1267A>G​(p.Ile423Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000108 in 1,610,392 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 Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I423R) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00058 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000058 (0 hom.)
• Consequence: GNE NM_005476.7 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:5 B:6
• Conservation: PhyloP100: 7.32
• Publications: 4 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: Benign. The variant received -8 ACMG points.

• 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 sialuria, GNE myopathy, congenital myopathy, platelet-type bleeding disorder 19, macrothrombocytopenia, isolated.
• BP4: Computational evidence support a benign effect (MetaRNN=0.04138413).
• BP6: Variant 9-36227262-T-C is Benign according to our data. Variant chr9-36227262-T-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 284451.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.000584 (89/152268) while in subpopulation AFR AF = 0.00207 (86/41550). AF 95% confidence interval is 0.00172. There are 0 homozygotes in GnomAd4. There are 43 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

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.1360A>G	p.Ile454Val	missense	Exon 7 of 12	NP_001121699.1
	GNE	NM_005476.7	MANE Select	c.1267A>G	p.Ile423Val	missense	Exon 7 of 12	NP_005467.1
	GNE	NM_001374797.1		c.1114A>G	p.Ile372Val	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.1360A>G	p.Ile454Val	missense	Exon 7 of 12	ENSP00000379839.3
	GNE	ENST00000642385.2	MANE Select	c.1267A>G	p.Ile423Val	missense	Exon 7 of 12	ENSP00000494141.2
	GNE	ENST00000543356.7	TSL:1	c.1090A>G	p.Ile364Val	missense	Exon 6 of 11	ENSP00000437765.3

Frequencies

GnomAD3 genomes AF: 0.000585 AC: 89 AN: 152150 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00208

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000139 AC: 35 AN: 251456 AF XY: 0.000118

Gnomad AFR exome AF: 0.00154

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000615

Gnomad OTH exome AF: 0.000326

GnomAD4 exome AF: 0.0000583 AC: 85 AN: 1458124 Hom.: 0 Cov.: 30 AF XY: 0.0000537 AC XY: 39 AN XY: 725672

African (AFR) AF: 0.00174 AC: 58 AN: 33372

American (AMR) AF: 0.0000447 AC: 2 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26114

East Asian (EAS) AF: 0.00 AC: 0 AN: 39684

South Asian (SAS) AF: 0.00 AC: 0 AN: 86154

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53418

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5756

European-Non Finnish (NFE) AF: 0.0000180 AC: 20 AN: 1108634

Other (OTH) AF: 0.0000830 AC: 5 AN: 60274

GnomAD4 genome AF: 0.000584 AC: 89 AN: 152268 Hom.: 0 Cov.: 32 AF XY: 0.000578 AC XY: 43 AN XY: 74458

African (AFR) AF: 0.00207 AC: 86 AN: 41550

American (AMR) AF: 0.0000654 AC: 1 AN: 15292

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5182

South Asian (SAS) AF: 0.00 AC: 0 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10614

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000294 AC: 2 AN: 68016

Other (OTH) AF: 0.00 AC: 0 AN: 2114

Alfa AF: 0.000660 Hom.: 0

Bravo AF: 0.000623

ESP6500AA AF: 0.00159 AC: 7

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.000222 AC: 27

EpiCase AF: 0.00

EpiControl AF: 0.000119

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	4	-	not provided (4)
-	1	1	GNE myopathy (2)
-	-	1	GNE-related disorder (1)
-	-	1	Inclusion Body Myopathy, Recessive (1)
-	-	1	not specified (1)
-	-	1	Sialuria (1)
-	-	1	Sialuria;C1853926:GNE myopathy (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.082
BayesDel_addAF	Benign	-0.067	T
BayesDel_noAF	Uncertain	0.13
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.66	D
Eigen	Benign	0.14
Eigen_PC	Uncertain	0.33
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.90	D
M_CAP	Pathogenic	0.53	D
MetaRNN	Benign	0.041	T
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Benign	-0.94	N
PhyloP100		7.3
PrimateAI	Uncertain	0.75	T
PROVEAN	Benign	-0.27	N
REVEL	Uncertain	0.53
Sift	Uncertain	0.0050	D
Sift4G	Benign	0.43	T
Polyphen		0.51	P
Vest4		0.52
MVP		0.87
MPC		0.70
ClinPred		0.044	T
GERP RS		6.0
Varity_R		0.43
gMVP		0.48
Mutation Taster		=36/64	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: rs35638832; hg19: chr9-36227259;