rs1554668704

Positions:

• chr9-36276942-C-T

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PVS1 PM2

The NM_001128227.3(GNE):​c.3G>A​(p.Met1?) variant causes a start lost change. The variant allele was found at a frequency of 0.000000685 in 1,460,908 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: GNE NM_001128227.3 start_lost
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.80

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]

LOC124902150 (HGNC:):

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

Verdict is Pathogenic. Variant got 10 ACMG points.

• PVS1: Start lost variant, no new inframe start found.
• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GNE	NM_001128227.3	c.3G>A	p.Met1?	start_lost	1/12	ENST00000396594.8
LOC124902150	XR_007061473.1	n.297-7766C>T		intron_variant, non_coding_transcript_variant
GNE	XM_005251334.5	c.3G>A	p.Met1?	start_lost	1/11
GNE	NM_001190388.2	c.-62G>A		5_prime_UTR_variant	1/11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GNE	ENST00000396594.8	c.3G>A	p.Met1?	start_lost	1/12	1	NM_001128227.3
GNE	ENST00000543356.7	c.-62G>A		5_prime_UTR_variant	1/11	1
GNE	ENST00000644762.1	n.35G>A		non_coding_transcript_exon_variant	1/2
CLTA	ENST00000464497.5	c.*101+11368C>T		intron_variant, NMD_transcript_variant		5

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1460908 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 726784

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.00e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 31

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

GNE myopathy Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Counsyl

Nov 19, 2017

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.18	D
BayesDel_noAF	Uncertain	0.030
CADD	Benign	23
DANN	Uncertain	0.99
Eigen	Uncertain	0.29
Eigen_PC	Uncertain	0.34
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Uncertain	0.90	D
MetaRNN	Pathogenic	0.98	D
MetaSVM	Benign	-0.34	T
MutationTaster	Benign	1.0	A;D
PROVEAN	Benign	-0.030	N
REVEL	Uncertain	0.57
Sift	Benign	0.051	T
Polyphen		0.66	P
Vest4		0.78
MutPred		0.88		Gain of catalytic residue at M1 (P = 0.0254);
MVP		0.97
ClinPred		0.52	D
GERP RS		6.0
gMVP		0.57

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs1554668704; hg19: chr9-36276939;