rs16933102

Positions:

• chr9-36227204-C-T

Variant summary

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

The NM_005476.7(GNE):​c.1281+44G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00725 in 1,230,326 control chromosomes in the GnomAD database, including 374 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.028 (201 hom., cov: 32)
  • Exomes 𝑓: 0.0043 (173 hom.)
• Consequence: GNE NM_005476.7 intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.143

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.88).
• BP6: Variant 9-36227204-C-T is Benign according to our data. Variant chr9-36227204-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 257523.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-36227204-C-T is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0913 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GNE	NM_001128227.3	c.1374+44G>A		intron_variant		ENST00000396594.8	NP_001121699.1
GNE	NM_005476.7	c.1281+44G>A		intron_variant		ENST00000642385.2	NP_005467.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GNE	ENST00000396594.8	c.1374+44G>A		intron_variant		1	NM_001128227.3	ENSP00000379839.3
GNE	ENST00000642385.2	c.1281+44G>A		intron_variant			NM_005476.7	ENSP00000494141.2

Frequencies

GnomAD3 genomes AF: 0.0283 AC: 4308 AN: 152034 Hom.: 200 Cov.: 32

Gnomad AFR AF: 0.0938

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0159

Gnomad ASJ AF: 0.00605

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.00622

Gnomad FIN AF: 0.0000945

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.00112

Gnomad OTH AF: 0.0244

GnomAD3 exomes AF: 0.00871 AC: 2136 AN: 245300 Hom.: 82 AF XY: 0.00711 AC XY: 944 AN XY: 132824

Gnomad AFR exome AF: 0.0953

Gnomad AMR exome AF: 0.00820

Gnomad ASJ exome AF: 0.00569

Gnomad EAS exome AF: 0.0000553

Gnomad SAS exome AF: 0.00555

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00114

Gnomad OTH exome AF: 0.00651

GnomAD4 exome AF: 0.00427 AC: 4606 AN: 1078174 Hom.: 173 Cov.: 15 AF XY: 0.00409 AC XY: 2265 AN XY: 553846

Gnomad4 AFR exome AF: 0.0982

Gnomad4 AMR exome AF: 0.00839

Gnomad4 ASJ exome AF: 0.00594

Gnomad4 EAS exome AF: 0.0000264

Gnomad4 SAS exome AF: 0.00600

Gnomad4 FIN exome AF: 0.0000188

Gnomad4 NFE exome AF: 0.000803

Gnomad4 OTH exome AF: 0.00874

GnomAD4 genome AF: 0.0284 AC: 4316 AN: 152152 Hom.: 201 Cov.: 32 AF XY: 0.0275 AC XY: 2049 AN XY: 74382

Gnomad4 AFR AF: 0.0938

Gnomad4 AMR AF: 0.0159

Gnomad4 ASJ AF: 0.00605

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00622

Gnomad4 FIN AF: 0.0000945

Gnomad4 NFE AF: 0.00110

Gnomad4 OTH AF: 0.0242

Alfa AF: 0.0268 Hom.: 38

Bravo AF: 0.0329

Asia WGS AF: 0.00924 AC: 32 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 18, 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. -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	2.7
DANN	Benign	0.65

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: rs16933102; hg19: chr9-36227201; COSMIC: COSV64953490;