chr9-36246500-T-C

Variant names:

• chr9-36246500-T-C
• rs374105190
• NM_001128227.3:c.258-18A>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BP6_Very_Strong

The NM_005476.7(GNE):​c.165-18A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000652 in 1,577,904 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 Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00037 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00068 (0 hom.)
• Consequence: GNE NM_005476.7 intron
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -0.496
• Publications: 0 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.75).
• BP6: Variant 9-36246500-T-C is Benign according to our data. Variant chr9-36246500-T-C is described in ClinVar as Likely_benign. ClinVar VariationId is 257525.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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.258-18A>G		intron	N/A	NP_001121699.1	Q9Y223-2
	GNE	NM_005476.7	MANE Select	c.165-18A>G		intron	N/A	NP_005467.1	Q9Y223-1
	GNE	NM_001374797.1		c.165-18A>G		intron	N/A	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.258-18A>G		intron	N/A	ENSP00000379839.3	Q9Y223-2
	GNE	ENST00000642385.2	MANE Select	c.165-18A>G		intron	N/A	ENSP00000494141.2	Q9Y223-1
	GNE	ENST00000543356.7	TSL:1	c.-13-18A>G		intron	N/A	ENSP00000437765.3	A0A7I2SU25

Frequencies

GnomAD3 genomes AF: 0.000369 AC: 56 AN: 151764 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000484

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000657

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000380

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000706

Gnomad OTH AF: 0.000480

GnomAD2 exomes AF: 0.000265 AC: 65 AN: 244986 AF XY: 0.000247

Gnomad AFR exome AF: 0.0000663

Gnomad AMR exome AF: 0.0000290

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000377

Gnomad NFE exome AF: 0.000502

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000682 AC: 973 AN: 1426140 Hom.: 0 Cov.: 26 AF XY: 0.000646 AC XY: 460 AN XY: 711878

African (AFR) AF: 0.0000609 AC: 2 AN: 32832

American (AMR) AF: 0.0000896 AC: 4 AN: 44646

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25882

East Asian (EAS) AF: 0.00 AC: 0 AN: 39540

South Asian (SAS) AF: 0.00 AC: 0 AN: 85460

European-Finnish (FIN) AF: 0.000327 AC: 17 AN: 51962

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4830

European-Non Finnish (NFE) AF: 0.000847 AC: 916 AN: 1081916

Other (OTH) AF: 0.000576 AC: 34 AN: 59072

GnomAD4 genome AF: 0.000369 AC: 56 AN: 151764 Hom.: 0 Cov.: 32 AF XY: 0.000351 AC XY: 26 AN XY: 74074

African (AFR) AF: 0.0000484 AC: 2 AN: 41284

American (AMR) AF: 0.0000657 AC: 1 AN: 15212

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5182

South Asian (SAS) AF: 0.00 AC: 0 AN: 4814

European-Finnish (FIN) AF: 0.000380 AC: 4 AN: 10540

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.000706 AC: 48 AN: 67954

Other (OTH) AF: 0.000480 AC: 1 AN: 2084

Alfa AF: 0.000256 Hom.: 0

Bravo AF: 0.000329

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not specified (3)
-	-	1	Sialuria;C1853926:GNE myopathy (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.75
CADD	Benign	7.3
DANN	Benign	0.62
PhyloP100		-0.50
Mutation Taster		=99/1	polymorphism

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

Other links and lift over

dbSNP: rs374105190; hg19: chr9-36246497;