9-36236977-A-C

Variant names:

• chr9-36236977-A-C
• rs35224402
• NM_001128227.3:c.717T>G

Variant summary

Our verdict is Benign. The variant received -15 ACMG points: 5P and 20B. PM1 PM5 PP2 BP4_Strong BP6_Very_Strong BS1 BS2

The NM_005476.7(GNE):​c.624T>G​(p.Asp208Glu) 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. D208G) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0036 (5 hom., cov: 32)
  • Exomes 𝑓: 0.00039 (6 hom.)
• Consequence: GNE NM_005476.7 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 2.27
• Publications: 5 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 -15 ACMG points.

• PM1: In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 8 uncertain in NM_005476.7
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr9-36236979-C-T is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 2136775.Status of the report is criteria_provided_single_submitter, 1 stars.
• PP2: Missense variant in the GNE gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 44 curated pathogenic missense variants (we use a threshold of 10). The gene has 1 curated benign missense variants. Gene score misZ: 2.5904 (below the threshold of 3.09). Trascript score misZ: 3.9915 (above the threshold of 3.09). GenCC associations: The gene is linked to sialuria, GNE myopathy, congenital myopathy, platelet-type bleeding disorder 19, macrothrombocytopenia, isolated.
• 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 Benign/Likely_benign. ClinVar VariationId is 287949.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00357 (544/152360) while in subpopulation AFR AF = 0.0122 (508/41590). AF 95% confidence interval is 0.0113. There are 5 homozygotes in GnomAd4. There are 253 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 5 AD,AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005476.7. 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.717T>G	p.Asp239Glu	missense	Exon 4 of 12	NP_001121699.1	Q9Y223-2
	GNE	NM_005476.7	MANE Select	c.624T>G	p.Asp208Glu	missense	Exon 4 of 12	NP_005467.1	Q9Y223-1
	GNE	NM_001190388.2		c.447T>G	p.Asp149Glu	missense	Exon 3 of 11	NP_001177317.2	A0A7I2SU25

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GNE	ENST00000396594.8	TSL:1 MANE Plus Clinical	c.717T>G	p.Asp239Glu	missense	Exon 4 of 12	ENSP00000379839.3	Q9Y223-2
	GNE	ENST00000642385.2	MANE Select	c.624T>G	p.Asp208Glu	missense	Exon 4 of 12	ENSP00000494141.2	Q9Y223-1
	GNE	ENST00000543356.7	TSL:1	c.447T>G	p.Asp149Glu	missense	Exon 3 of 11	ENSP00000437765.3	A0A7I2SU25

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

GnomAD2 exomes AF: 0.000896 AC: 225 AN: 251226 AF XY: 0.000604

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 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

African (AFR) AF: 0.0143 AC: 479 AN: 33388

American (AMR) AF: 0.000738 AC: 33 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26088

East Asian (EAS) AF: 0.00 AC: 0 AN: 39634

South Asian (SAS) AF: 0.0000812 AC: 7 AN: 86172

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53346

Middle Eastern (MID) AF: 0.000529 AC: 3 AN: 5670

European-Non Finnish (NFE) AF: 0.00000180 AC: 2 AN: 1108252

Other (OTH) AF: 0.000846 AC: 51 AN: 60252

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

African (AFR) AF: 0.0122 AC: 508 AN: 41590

American (AMR) AF: 0.00190 AC: 29 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5194

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4834

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10626

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000441 AC: 3 AN: 68036

Other (OTH) AF: 0.00142 AC: 3 AN: 2114

Alfa AF: 0.00196 Hom.: 4

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

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	2	not specified (2)
-	-	2	Sialuria;C1853926:GNE myopathy (2)
-	-	1	See cases (1)

Computational scores

Source: dbNSFP v4.9

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
Eigen	Benign	-0.077
Eigen_PC	Benign	0.13
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Uncertain	0.96	D
MetaRNN	Benign	0.010	T
MetaSVM	Uncertain	0.75	D
MutationAssessor	Benign	0.72	N
PhyloP100		2.3
PrimateAI	Uncertain	0.52	T
PROVEAN	Benign	-0.50	N
REVEL	Uncertain	0.45
Sift	Benign	0.46	T
Sift4G	Benign	1.0	T
Polyphen		0.0	B
Vest4		0.51
MutPred		0.56		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
Mutation Taster		=63/37	polymorphism

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

Other links and lift over

dbSNP: rs35224402; hg19: chr9-36236974;