rs7047950

chr9-36246047-G-A

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BA1

The NM_001128227.3(GNE):c.693C>T(p.Ile231=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.006 in 1,613,574 control chromosomes in the GnomAD database, including 376 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.027 (183 hom., cov: 32)
  • Exomes 𝑓: 0.0038 (193 hom.)
• Consequence: GNE NM_001128227.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: 2.21

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

Verdict is Benign. Variant got -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.42).
• BP6: Variant 9-36246047-G-A is Benign according to our data. Variant chr9-36246047-G-A is described in ClinVar as [Benign]. Clinvar id is 196411.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-36246047-G-A is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=2.21 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.087 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GNE	NM_001128227.3	c.693C>T	p.Ile231=	synonymous_variant	3/12	ENST00000396594.8
GNE	NM_005476.7	c.600C>T	p.Ile200=	synonymous_variant	3/12	ENST00000642385.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GNE	ENST00000396594.8	c.693C>T	p.Ile231=	synonymous_variant	3/12	1	NM_001128227.3
GNE	ENST00000642385.2	c.600C>T	p.Ile200=	synonymous_variant	3/12		NM_005476.7	P1

Frequencies

GnomAD3 genomes AF: 0.0269 AC: 4098 AN: 152226 Hom.: 182 Cov.: 32

Gnomad AFR AF: 0.0893

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0145

Gnomad ASJ AF: 0.00605

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.00620

Gnomad FIN AF: 0.0000941

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.00106

Gnomad OTH AF: 0.0220

GnomAD3 exomes AF: 0.00843 AC: 2118 AN: 251312 Hom.: 77 AF XY: 0.00694 AC XY: 942 AN XY: 135824

Gnomad AFR exome AF: 0.0904

Gnomad AMR exome AF: 0.00755

Gnomad ASJ exome AF: 0.00586

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.00555

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00106

Gnomad OTH exome AF: 0.00587

GnomAD4 exome AF: 0.00381 AC: 5569 AN: 1461230 Hom.: 193 Cov.: 33 AF XY: 0.00371 AC XY: 2695 AN XY: 726954

Gnomad4 AFR exome AF: 0.0952

Gnomad4 AMR exome AF: 0.00787

Gnomad4 ASJ exome AF: 0.00628

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00596

Gnomad4 FIN exome AF: 0.0000188

Gnomad4 NFE exome AF: 0.000731

Gnomad4 OTH exome AF: 0.00785

GnomAD4 genome AF: 0.0270 AC: 4111 AN: 152344 Hom.: 183 Cov.: 32 AF XY: 0.0261 AC XY: 1946 AN XY: 74508

Gnomad4 AFR AF: 0.0894

Gnomad4 AMR AF: 0.0145

Gnomad4 ASJ AF: 0.00605

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00621

Gnomad4 FIN AF: 0.0000941

Gnomad4 NFE AF: 0.00104

Gnomad4 OTH AF: 0.0218

Alfa AF: 0.00859 Hom.: 57

Bravo AF: 0.0312

Asia WGS AF: 0.00866 AC: 30 AN: 3478

EpiCase AF: 0.00153

EpiControl AF: 0.00166

ClinVar

Significance: Benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Benign, criteria provided, single submitter	clinical testing	GeneDx	May 24, 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)	Aug 24, 2016	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

GNE myopathy Benign:2

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jun 14, 2016	- -
Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -

Sialuria Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Sialuria;C1853926:GNE myopathy Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 31, 2024

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Athena Diagnostics

Feb 14, 2020

- -

Inclusion Body Myopathy, Recessive Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.42
Cadd	Benign	6.7
Dann	Benign	0.84

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

Publications

LitVar

Other links and lift over

dbSNP: rs7047950; hg19: chr9-36246044;