rs35638832

Positions:

chr9-36227262-T-C

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 1P and 5B. PP2BP4_StrongBP6

The NM_001128227.3(GNE):c.1360A>G(p.Ile454Val) 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. I454R) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00058 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000058 ( 0 hom. )

Consequence

GNE
NM_001128227.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:5B:6

Conservation

PhyloP100: 7.32

Variant links:

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 links:

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]

CLTA links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -4 ACMG points.

PP2

Missense variant in gene, where missense usually causes diseases (based on misZ statistic), GNE. . Gene score misZ 2.5904 (greater than the threshold 3.09). Trascript score misZ 4.032 (greater than threshold 3.09). GenCC has associacion of gene with macrothrombocytopenia, isolated, platelet-type bleeding disorder 19, sialuria, GNE myopathy.

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 id is 284451.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=5, Uncertain_significance=4, Benign=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GNE	NM_001128227.3 linkuse as main transcript	c.1360A>G	p.Ile454Val	missense_variant	7/12	ENST00000396594.8
GNE	NM_005476.7 linkuse as main transcript	c.1267A>G	p.Ile423Val	missense_variant	7/12	ENST00000642385.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GNE	ENST00000396594.8 linkuse as main transcript	c.1360A>G	p.Ile454Val	missense_variant	7/12	1	NM_001128227.3		Q9Y223-2
GNE	ENST00000642385.2 linkuse as main transcript	c.1267A>G	p.Ile423Val	missense_variant	7/12		NM_005476.7	P1	Q9Y223-1

Frequencies

GnomAD3 genomes

AF:

0.000585

AC:

AN:

152150

Hom.:

Cov.:

show subpopulations

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

GnomAD3 exomes

AF:

0.000139

AC:

AN:

251456

Hom.:

AF XY:

0.000118

AC XY:

AN XY:

135902

show subpopulations

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 SAS 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:

AN:

1458124

Hom.:

Cov.:

AF XY:

0.0000537

AC XY:

AN XY:

725672

show subpopulations

Gnomad4 AFR exome

AF:

0.00174

Gnomad4 AMR exome

AF:

0.0000447

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:

0.0000180

Gnomad4 OTH exome

AF:

0.0000830

GnomAD4 genome

AF:

0.000584

AC:

AN:

152268

Hom.:

Cov.:

AF XY:

0.000578

AC XY:

AN XY:

74458

show subpopulations

Gnomad4 AFR

AF:

0.00207

Gnomad4 AMR

AF:

0.0000654

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000294

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000584

Hom.:

Bravo

AF:

0.000623

ESP6500AA

AF:

0.00159

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.000222

AC:

EpiCase

AF:

0.00

EpiControl

AF:

0.000119

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:5Benign:6

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:4

Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Feb 28, 2017	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Apr 27, 2023	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Oct 15, 2019	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Feb 09, 2023	In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -

GNE myopathy

Uncertain:1Benign:1

Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jun 14, 2016	- -
Uncertain significance, no assertion criteria provided	clinical testing	Natera, Inc.	Jan 08, 2020	- -

not specified

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Sep 07, 2023

Variant summary: GNE c.1360A>G (p.Ile454Val) results in a conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00019 in 282854 control chromosomes (gnomAD), predominantly at a frequency of 0.0017 within the African or African-American subpopulation in the gnomAD database. The observed variant frequency within African or African-American control individuals in the gnomAD database is approximately 1.5 fold of the estimated maximal expected allele frequency for a pathogenic variant in GNE causing Inclusion Body Myopathy 2 (0.0011), suggesting that the variant is a benign polymorphism found primarily in populations of African or African-American origin. To our knowledge, no occurrence of c.1360A>G in individuals affected with Inclusion Body Myopathy 2 and no experimental evidence demonstrating its impact on protein function have been reported. Seven ClinVar submitters have assessed the variant since 2014: four classified the variant as uncertain significance, two as likely benign, and one as benign. Based on the evidence outlined above, the variant was classified as likely benign. -

Sialuria

Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 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

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Jan 13, 2024

- -

GNE-related disorder

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Nov 13, 2022

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Inclusion Body Myopathy, Recessive

Benign:1

Likely 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

AlphaMissense

Benign

0.082

BayesDel_addAF

Benign

-0.067

BayesDel_noAF

Uncertain

0.13

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.66

D;.;D;.;.;.;D

Eigen

Benign

0.14

Eigen_PC

Uncertain

0.33

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.90

.;D;D;D;D;D;.

M_CAP

Pathogenic

0.53

MetaRNN

Benign

0.041

T;T;T;T;T;T;T

MetaSVM

Pathogenic

1.1

MutationAssessor

Benign

-0.94

N;.;N;.;.;N;N

MutationTaster

Benign

1.0

D;D;D;D;D;D

PrimateAI

Uncertain

0.75

PROVEAN

Benign

-0.27

.;N;N;N;N;N;N

REVEL

Uncertain

0.53

Sift

Uncertain

0.0050

.;D;D;D;T;D;D

Sift4G

Benign

0.43

.;T;T;T;T;T;T

Polyphen

0.51

P;P;P;.;.;.;P

Vest4

0.52, 0.51, 0.50, 0.46

MVP

0.87

MPC

0.70

ClinPred

0.044

GERP RS

6.0

Varity_R

0.43

gMVP

0.48

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over