rs7875447

chr9-36276860-A-Gchr9-36276860-A-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001128227.3(GNE):c.51+34T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.772 in 1,517,118 control chromosomes in the GnomAD database, including 456,607 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.75 (43298 hom., cov: 31)
  • Exomes 𝑓: 0.77 (413309 hom.)
• Consequence: GNE NM_001128227.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -1.82

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 Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BP6: Variant 9-36276860-A-G is Benign according to our data. Variant chr9-36276860-A-G is described in ClinVar as [Benign]. Clinvar id is 257526.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.799 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GNE	NM_001128227.3	c.51+34T>C		intron_variant		ENST00000396594.8
LOC124902150	XR_007061473.1	n.297-7848A>G		intron_variant, non_coding_transcript_variant
GNE	NM_001190388.2	c.-14+34T>C		intron_variant
GNE	XM_005251334.5	c.51+34T>C		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GNE	ENST00000396594.8	c.51+34T>C		intron_variant		1	NM_001128227.3
GNE	ENST00000543356.7	c.-14+34T>C		intron_variant		1
CLTA	ENST00000464497.5	c.*101+11286A>G		intron_variant, NMD_transcript_variant		5
GNE	ENST00000644762.1	n.83+34T>C		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes AF: 0.751 AC: 114022 AN: 151918 Hom.: 43261 Cov.: 31

Gnomad AFR AF: 0.738

Gnomad AMI AF: 0.884

Gnomad AMR AF: 0.683

Gnomad ASJ AF: 0.779

Gnomad EAS AF: 0.466

Gnomad SAS AF: 0.659

Gnomad FIN AF: 0.716

Gnomad MID AF: 0.684

Gnomad NFE AF: 0.804

Gnomad OTH AF: 0.755

GnomAD3 exomes AF: 0.727 AC: 166817 AN: 229436 Hom.: 61922 AF XY: 0.732 AC XY: 91464 AN XY: 125016

Gnomad AFR exome AF: 0.738

Gnomad AMR exome AF: 0.616

Gnomad ASJ exome AF: 0.781

Gnomad EAS exome AF: 0.455

Gnomad SAS exome AF: 0.684

Gnomad FIN exome AF: 0.729

Gnomad NFE exome AF: 0.801

Gnomad OTH exome AF: 0.758

GnomAD4 exome AF: 0.774 AC: 1057189 AN: 1365082 Hom.: 413309 Cov.: 20 AF XY: 0.773 AC XY: 527823 AN XY: 682896

Gnomad4 AFR exome AF: 0.729

Gnomad4 AMR exome AF: 0.623

Gnomad4 ASJ exome AF: 0.780

Gnomad4 EAS exome AF: 0.464

Gnomad4 SAS exome AF: 0.687

Gnomad4 FIN exome AF: 0.733

Gnomad4 NFE exome AF: 0.803

Gnomad4 OTH exome AF: 0.757

GnomAD4 genome AF: 0.751 AC: 114115 AN: 152036 Hom.: 43298 Cov.: 31 AF XY: 0.743 AC XY: 55249 AN XY: 74310

Gnomad4 AFR AF: 0.737

Gnomad4 AMR AF: 0.682

Gnomad4 ASJ AF: 0.779

Gnomad4 EAS AF: 0.467

Gnomad4 SAS AF: 0.660

Gnomad4 FIN AF: 0.716

Gnomad4 NFE AF: 0.804

Gnomad4 OTH AF: 0.758

Alfa AF: 0.777 Hom.: 8182

Bravo AF: 0.745

Asia WGS AF: 0.618 AC: 2150 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Apr 30, 2021	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

GNE myopathy Benign:2

Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Jan 03, 2020	- -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 10, 2021	- -

Sialuria Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 10, 2021

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Jun 14, 2018

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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
Cadd	Benign	0.052
Dann	Benign	0.68

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs7875447; hg19: chr9-36276857; COSMIC: COSV67454188;