chr9-36276954-C-T

Position:

• chr9-36276954-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001128227.3(GNE):​c.-10G>A variant causes a 5 prime UTR premature start codon gain change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00162 in 1,613,054 control chromosomes in the GnomAD database, including 35 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0082 (19 hom., cov: 31)
  • Exomes 𝑓: 0.00094 (16 hom.)
• Consequence: GNE NM_001128227.3 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: -0.815

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]

GNE (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 Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0037608743).
• BP6: Variant 9-36276954-C-T is Benign according to our data. Variant chr9-36276954-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 257520.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-36276954-C-T is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00815 (1241/152192) while in subpopulation AFR AF= 0.0285 (1181/41510). AF 95% confidence interval is 0.0271. There are 19 homozygotes in gnomad4. There are 579 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 19 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GNE	NM_001128227.3	c.-10G>A		5_prime_UTR_premature_start_codon_gain_variant	1/12	ENST00000396594.8	NP_001121699.1
GNE	NM_001128227.3	c.-10G>A		5_prime_UTR_variant	1/12	ENST00000396594.8	NP_001121699.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GNE	ENST00000396594.8	c.-10G>A		5_prime_UTR_premature_start_codon_gain_variant	1/12	1	NM_001128227.3	ENSP00000379839.3
GNE	ENST00000396594.8	c.-10G>A		5_prime_UTR_variant	1/12	1	NM_001128227.3	ENSP00000379839.3

Frequencies

GnomAD3 genomes AF: 0.00818 AC: 1244 AN: 152074 Hom.: 19 Cov.: 31

Gnomad AFR AF: 0.0286

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00249

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00186

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000735

Gnomad OTH AF: 0.00432

GnomAD3 exomes AF: 0.00214 AC: 531 AN: 248394 Hom.: 12 AF XY: 0.00164 AC XY: 222 AN XY: 134990

Gnomad AFR exome AF: 0.0275

Gnomad AMR exome AF: 0.00108

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00193

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000533

Gnomad OTH exome AF: 0.000997

GnomAD4 exome AF: 0.000936 AC: 1367 AN: 1460862 Hom.: 16 Cov.: 30 AF XY: 0.000874 AC XY: 635 AN XY: 726742

Gnomad4 AFR exome AF: 0.0297

Gnomad4 AMR exome AF: 0.00137

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00187

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000270

Gnomad4 OTH exome AF: 0.00186

GnomAD4 genome AF: 0.00815 AC: 1241 AN: 152192 Hom.: 19 Cov.: 31 AF XY: 0.00778 AC XY: 579 AN XY: 74406

Gnomad4 AFR AF: 0.0285

Gnomad4 AMR AF: 0.00249

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00166

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000735

Gnomad4 OTH AF: 0.00427

Alfa AF: 0.00163 Hom.: 4

Bravo AF: 0.00920

TwinsUK AF: 0.000809 AC: 3

ALSPAC AF: 0.00 AC: 0

ESP6500AA AF: 0.0290 AC: 91

ESP6500EA AF: 0.000279 AC: 2

ExAC AF: 0.00277 AC: 334

Asia WGS AF: 0.00433 AC: 16 AN: 3478

EpiCase AF: 0.0000545

EpiControl AF: 0.0000594

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Benign, criteria provided, single submitter	clinical testing	GeneDx	May 18, 2016	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Sep 06, 2016	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

Sialuria;C1853926:GNE myopathy Benign:2

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 18, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Apr 07, 2022	- -

not provided Benign:2

Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Sep 08, 2016	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.43	T
BayesDel_noAF	Benign	-0.36
CADD	Benign	10
DANN	Benign	0.72
Eigen	Benign	-0.72
Eigen_PC	Benign	-0.80
FATHMM_MKL	Benign	0.021	N
LIST_S2	Benign	0.32	T
MetaRNN	Benign	0.0038	T
MetaSVM	Benign	-1.0	T
REVEL	Benign	0.027
Sift4G	Benign	0.37	T
Vest4		0.28
MVP		0.86
ClinPred		0.0032	T
GERP RS		1.2

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs73449614; hg19: chr9-36276951;