rs35224402

Positions:

• chr9-36236977-A-C

Variant summary

Our verdict is Benign. Variant got -11 ACMG points: 5P and 16B. PM1 PM5 PP2 BP4_Strong BP6_Very_Strong BS2

The NM_001128227.3(GNE):​c.717T>G​(p.Asp239Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000695 in 1,609,878 control chromosomes in the GnomAD database, including 11 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D239A) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0036 (5 hom., cov: 32)
  • Exomes 𝑓: 0.00039 (6 hom.)
• Consequence: GNE NM_001128227.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 2.27

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 -11 ACMG points.

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 4 uncertain in NM_001128227.3
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr9-36236979-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 2136775.Status of the report is criteria_provided_single_submitter, 1 stars.
• 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=0.010086775).
• BP6: Variant 9-36236977-A-C is Benign according to our data. Variant chr9-36236977-A-C is described in ClinVar as [Likely_benign]. Clinvar id is 287949.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-36236977-A-C is described in Lovd as [Pathogenic].
• BS2: High Homozygotes in GnomAd4 at 5 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GNE	NM_001128227.3	c.717T>G	p.Asp239Glu	missense_variant	4/12	ENST00000396594.8
GNE	NM_005476.7	c.624T>G	p.Asp208Glu	missense_variant	4/12	ENST00000642385.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GNE	ENST00000396594.8	c.717T>G	p.Asp239Glu	missense_variant	4/12	1	NM_001128227.3
GNE	ENST00000642385.2	c.624T>G	p.Asp208Glu	missense_variant	4/12		NM_005476.7	P1

Frequencies

GnomAD3 genomes AF: 0.00355 AC: 541 AN: 152242 Hom.: 5 Cov.: 32

Gnomad AFR AF: 0.0122

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00190

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000413

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000441

Gnomad OTH AF: 0.00143

GnomAD3 exomes AF: 0.000896 AC: 225 AN: 251226 Hom.: 3 AF XY: 0.000604 AC XY: 82 AN XY: 135782

Gnomad AFR exome AF: 0.0120

Gnomad AMR exome AF: 0.000752

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000654

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000880

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.000395 AC: 575 AN: 1457518 Hom.: 6 Cov.: 28 AF XY: 0.000323 AC XY: 234 AN XY: 725410

Gnomad4 AFR exome AF: 0.0143

Gnomad4 AMR exome AF: 0.000738

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000812

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000180

Gnomad4 OTH exome AF: 0.000846

GnomAD4 genome AF: 0.00357 AC: 544 AN: 152360 Hom.: 5 Cov.: 32 AF XY: 0.00340 AC XY: 253 AN XY: 74510

Gnomad4 AFR AF: 0.0122

Gnomad4 AMR AF: 0.00190

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000441

Gnomad4 OTH AF: 0.00142

Alfa AF: 0.00134 Hom.: 0

Bravo AF: 0.00428

ESP6500AA AF: 0.0136 AC: 60

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000914 AC: 111

Asia WGS AF: 0.00202 AC: 7 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Oct 01, 2022	GNE: BS1, BS2 -
Likely benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Dec 31, 2018	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 13, 2020	This variant is associated with the following publications: (PMID: 24796702, 27858732, 33094863) -

Sialuria;C1853926:GNE myopathy Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Nov 23, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 29, 2024	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Eurofins Ntd Llc (ga)

May 24, 2016

- -

See cases Benign:1

Benign, criteria provided, single submitter

clinical testing

Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein

Feb 25, 2020

ACMG classification criteria: BS1, BS2 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.081
BayesDel_addAF	Benign	-0.21	T
BayesDel_noAF	Uncertain	-0.070
CADD	Benign	17
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.77	D;.;D;.;.;D
Eigen	Benign	-0.077
Eigen_PC	Benign	0.13
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Uncertain	0.96	.;D;D;D;D;.
MetaRNN	Benign	0.010	T;T;T;T;T;T
MetaSVM	Uncertain	0.75	D
MutationAssessor	Benign	0.72	N;.;N;.;N;N
MutationTaster	Benign	1.0	D;D;D;D;D;D
PrimateAI	Uncertain	0.52	T
PROVEAN	Benign	-0.50	.;N;N;.;N;N
REVEL	Uncertain	0.45
Sift	Benign	0.46	.;T;T;.;T;T
Sift4G	Benign	1.0	.;T;T;T;T;T
Polyphen		0.0	B;B;B;.;.;B
Vest4		0.51, 0.44, 0.48, 0.48, 0.43
MutPred		0.56		Gain of methylation at K210 (P = 0.08);.;Gain of methylation at K210 (P = 0.08);.;Gain of methylation at K210 (P = 0.08);Gain of methylation at K210 (P = 0.08);
MVP		1.0
MPC		0.50
ClinPred		0.014	T
GERP RS		6.1
Varity_R		0.12
gMVP		0.64

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs35224402; hg19: chr9-36236974;