rs111302956

Variant names:

• chr9-36219884-G-A
• rs111302956
• NM_001128227.3:c.1863C>T

Your query was ambiguous. Multiple possible variants found:

• chr9-36219884-G-A
• chr9-36219884-G-T

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_001128227.3(GNE):​c.1863C>T​(p.Tyr621Tyr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0198 in 1,614,008 control chromosomes in the GnomAD database, including 411 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.016 (38 hom., cov: 32)
  • Exomes 𝑓: 0.020 (373 hom.)
• Consequence: GNE NM_001128227.3 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:12
• Conservation: PhyloP100: 0.825
• Publications: 4 publications found

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

Our verdict: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.57).
• BP6: Variant 9-36219884-G-A is Benign according to our data. Variant chr9-36219884-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 95282.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.825 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0164 (2503/152230) while in subpopulation NFE AF = 0.0243 (1651/68010). AF 95% confidence interval is 0.0233. There are 38 homozygotes in GnomAd4. There are 1257 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 38 AD,AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001128227.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GNE	NM_001128227.3	MANE Plus Clinical	c.1863C>T	p.Tyr621Tyr	synonymous	Exon 10 of 12	NP_001121699.1
	GNE	NM_005476.7	MANE Select	c.1770C>T	p.Tyr590Tyr	synonymous	Exon 10 of 12	NP_005467.1
	GNE	NM_001374797.1		c.1617C>T	p.Tyr539Tyr	synonymous	Exon 9 of 11	NP_001361726.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GNE	ENST00000396594.8	TSL:1 MANE Plus Clinical	c.1863C>T	p.Tyr621Tyr	synonymous	Exon 10 of 12	ENSP00000379839.3
	GNE	ENST00000642385.2	MANE Select	c.1770C>T	p.Tyr590Tyr	synonymous	Exon 10 of 12	ENSP00000494141.2
	GNE	ENST00000543356.7	TSL:1	c.1593C>T	p.Tyr531Tyr	synonymous	Exon 9 of 11	ENSP00000437765.3

Frequencies

GnomAD3 genomes AF: 0.0165 AC: 2503 AN: 152112 Hom.: 38 Cov.: 32

Gnomad AFR AF: 0.00420

Gnomad AMI AF: 0.0451

Gnomad AMR AF: 0.00772

Gnomad ASJ AF: 0.0257

Gnomad EAS AF: 0.000385

Gnomad SAS AF: 0.0120

Gnomad FIN AF: 0.0317

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.0243

Gnomad OTH AF: 0.0139

GnomAD2 exomes AF: 0.0180 AC: 4536 AN: 251476 AF XY: 0.0190

Gnomad AFR exome AF: 0.00455

Gnomad AMR exome AF: 0.00439

Gnomad ASJ exome AF: 0.0223

Gnomad EAS exome AF: 0.000163

Gnomad FIN exome AF: 0.0360

Gnomad NFE exome AF: 0.0236

Gnomad OTH exome AF: 0.0205

GnomAD4 exome AF: 0.0201 AC: 29408 AN: 1461778 Hom.: 373 Cov.: 32 AF XY: 0.0204 AC XY: 14805 AN XY: 727194

African (AFR) AF: 0.00358 AC: 120 AN: 33478

American (AMR) AF: 0.00467 AC: 209 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0231 AC: 605 AN: 26136

East Asian (EAS) AF: 0.000101 AC: 4 AN: 39698

South Asian (SAS) AF: 0.0178 AC: 1532 AN: 86258

European-Finnish (FIN) AF: 0.0359 AC: 1919 AN: 53412

Middle Eastern (MID) AF: 0.0133 AC: 77 AN: 5768

European-Non Finnish (NFE) AF: 0.0215 AC: 23896 AN: 1111914

Other (OTH) AF: 0.0173 AC: 1046 AN: 60390

GnomAD4 genome AF: 0.0164 AC: 2503 AN: 152230 Hom.: 38 Cov.: 32 AF XY: 0.0169 AC XY: 1257 AN XY: 74442

African (AFR) AF: 0.00419 AC: 174 AN: 41544

American (AMR) AF: 0.00771 AC: 118 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.0257 AC: 89 AN: 3468

East Asian (EAS) AF: 0.000386 AC: 2 AN: 5184

South Asian (SAS) AF: 0.0122 AC: 59 AN: 4818

European-Finnish (FIN) AF: 0.0317 AC: 336 AN: 10590

Middle Eastern (MID) AF: 0.0136 AC: 4 AN: 294

European-Non Finnish (NFE) AF: 0.0243 AC: 1651 AN: 68010

Other (OTH) AF: 0.0137 AC: 29 AN: 2112

Alfa AF: 0.0182 Hom.: 33

Bravo AF: 0.0136

Asia WGS AF: 0.00520 AC: 18 AN: 3478

EpiCase AF: 0.0207

EpiControl AF: 0.0196

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	not specified (5)
-	-	2	GNE myopathy (2)
-	-	2	not provided (2)
-	-	1	Inclusion Body Myopathy, Recessive (1)
-	-	1	Sialuria (1)
-	-	1	Sialuria;C1853926:GNE myopathy (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.57
CADD	Benign	8.5
DANN	Benign	0.79
PhyloP100		0.82
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs111302956; hg19: chr9-36219881;