9-36276954-C-T

Variant names:

• chr9-36276954-C-T
• rs73449614
• NM_001128227.3:c.-10G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001128227.3(GNE):​c.-10G>A variant causes a 5 prime UTR premature start codon gain change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00162 in 1,613,054 control chromosomes in the GnomAD database, including 35 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0082 (19 hom., cov: 31)
  • Exomes 𝑓: 0.00094 (16 hom.)
• Consequence: GNE NM_001128227.3 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: -0.815
• Publications: 2 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]

LOC124902150 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0037608743).
• BP6: Variant 9-36276954-C-T is Benign according to our data. Variant chr9-36276954-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 257520.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 = 0.00815 (1241/152192) while in subpopulation AFR AF = 0.0285 (1181/41510). AF 95% confidence interval is 0.0271. There are 19 homozygotes in GnomAd4. There are 579 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 19 AR,AD 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.-10G>A		5_prime_UTR_premature_start_codon_gain	Exon 1 of 12	NP_001121699.1	Q9Y223-2
	GNE	NM_001128227.3	MANE Plus Clinical	c.-10G>A		5_prime_UTR	Exon 1 of 12	NP_001121699.1	Q9Y223-2
	GNE	NM_001190388.2		c.-74G>A		5_prime_UTR_premature_start_codon_gain	Exon 1 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.-10G>A		5_prime_UTR_premature_start_codon_gain	Exon 1 of 12	ENSP00000379839.3	Q9Y223-2
	GNE	ENST00000543356.7	TSL:1	c.-74G>A		5_prime_UTR_premature_start_codon_gain	Exon 1 of 11	ENSP00000437765.3	A0A7I2SU25
	GNE	ENST00000396594.8	TSL:1 MANE Plus Clinical	c.-10G>A		5_prime_UTR	Exon 1 of 12	ENSP00000379839.3	Q9Y223-2

Frequencies

GnomAD3 genomes AF: 0.00818 AC: 1244 AN: 152074 Hom.: 19 Cov.: 31

Gnomad AFR AF: 0.0286

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00249

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00186

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000735

Gnomad OTH AF: 0.00432

GnomAD2 exomes AF: 0.00214 AC: 531 AN: 248394 AF XY: 0.00164

Gnomad AFR exome AF: 0.0275

Gnomad AMR exome AF: 0.00108

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000533

Gnomad OTH exome AF: 0.000997

GnomAD4 exome AF: 0.000936 AC: 1367 AN: 1460862 Hom.: 16 Cov.: 30 AF XY: 0.000874 AC XY: 635 AN XY: 726742

African (AFR) AF: 0.0297 AC: 993 AN: 33428

American (AMR) AF: 0.00137 AC: 61 AN: 44650

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26124

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39652

South Asian (SAS) AF: 0.00187 AC: 161 AN: 86166

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53398

Middle Eastern (MID) AF: 0.00156 AC: 9 AN: 5764

European-Non Finnish (NFE) AF: 0.0000270 AC: 30 AN: 1111348

Other (OTH) AF: 0.00186 AC: 112 AN: 60332

GnomAD4 genome AF: 0.00815 AC: 1241 AN: 152192 Hom.: 19 Cov.: 31 AF XY: 0.00778 AC XY: 579 AN XY: 74406

African (AFR) AF: 0.0285 AC: 1181 AN: 41510

American (AMR) AF: 0.00249 AC: 38 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5176

South Asian (SAS) AF: 0.00166 AC: 8 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10610

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

European-Non Finnish (NFE) AF: 0.0000735 AC: 5 AN: 68016

Other (OTH) AF: 0.00427 AC: 9 AN: 2106

Alfa AF: 0.00337 Hom.: 8

Bravo AF: 0.00920

TwinsUK AF: 0.000809 AC: 3

ALSPAC AF: 0.00 AC: 0

ESP6500AA AF: 0.0290 AC: 91

ESP6500EA AF: 0.000279 AC: 2

ExAC AF: 0.00277 AC: 334

Asia WGS AF: 0.00433 AC: 16 AN: 3478

EpiCase AF: 0.0000545

EpiControl AF: 0.0000594

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not specified (3)
-	-	2	not provided (2)
-	-	2	Sialuria;C1853926:GNE myopathy (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.17
BayesDel_addAF	Benign	-0.43	T
BayesDel_noAF	Benign	-0.36
CADD	Benign	10
DANN	Benign	0.72
Eigen	Benign	-0.72
Eigen_PC	Benign	-0.80
FATHMM_MKL	Benign	0.021	N
LIST_S2	Benign	0.32	T
MetaRNN	Benign	0.0038	T
MetaSVM	Benign	-1.0	T
PhyloP100		-0.81
REVEL	Benign	0.027
Sift4G	Benign	0.37	T
Vest4		0.28
MVP		0.86
ClinPred		0.0032	T
GERP RS		1.2
PromoterAI		-0.00030	Neutral
Mutation Taster		=93/7	polymorphism

Splicing

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

Other links and lift over

dbSNP: rs73449614; hg19: chr9-36276951;