Genetic Variant GNPTG:p.Leu8_Leu9insAlaArgLeu (chr16-1351975-G-GGGCTGGCGC) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_032520.5(GNPTG):c.15_23dupGGCGCGGCT(p.Leu8_Leu9insAlaArgLeu) variant causes a disruptive inframe insertion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000014 in 1,210,982 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. L8L) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.000014 ( 0 hom. )

Consequence

GNPTG
NM_032520.5 disruptive_inframe_insertion

Scores

Not classified

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -0.647

Publications

3 publications found

Variant links:

Genes affected

GNPTG (HGNC:23026): (N-acetylglucosamine-1-phosphate transferase subunit gamma) This gene encodes the gamma sunbunit of the N-acetylglucosamine-1-phosphotransferase complex. This hexameric complex, composed of alpha, beta and gamma subunits, catalyzes the first step in synthesis of a mannose 6-phosphate lysosomal recognition marker. This enzyme complex is necessary for targeting of lysosomal hydrolases to the lysosome. Mutations in the gene encoding the gamma subunit have been associated with mucolipidosis IIIC, also known as mucolipidosis III gamma.[provided by RefSeq, Feb 2010]

GNPTG links:

TSR3 (HGNC:14175): (TSR3 ribosome maturation factor) Enables transferase activity. Involved in enzyme-directed rRNA pseudouridine synthesis. Predicted to be located in cytosol. [provided by Alliance of Genome Resources, Apr 2022]

TSR3 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_032520.5. 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
	GNPTG	NM_032520.5	MANE Select	c.15_23dupGGCGCGGCT	p.Leu8_Leu9insAlaArgLeu	disruptive_inframe_insertion	Exon 1 of 11	NP_115909.1	Q9UJJ9
	TSR3	NM_001001410.3	MANE Select	c.-180_-172dupGCGCCAGCC		upstream_gene	N/A	NP_001001410.1	Q9UJK0

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
GNPTG	ENST00000204679.9	TSL:1 MANE Select	c.15_23dupGGCGCGGCT	p.Leu8_Leu9insAlaArgLeu	disruptive_inframe_insertion	Exon 1 of 11	ENSP00000204679.4	Q9UJJ9
GNPTG	ENST00000891792.1		c.15_23dupGGCGCGGCT	p.Leu8_Leu9insAlaArgLeu	disruptive_inframe_insertion	Exon 1 of 12	ENSP00000561851.1
GNPTG	ENST00000529110.2	TSL:2	c.15_23dupGGCGCGGCT	p.Leu8_Leu9insAlaArgLeu	disruptive_inframe_insertion	Exon 1 of 10	ENSP00000435349.2	H0YEA7

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.0000140

AC:

AN:

1210982

Hom.:

Cov.:

AF XY:

0.00000678

AC XY:

AN XY:

590180

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

24380

American (AMR)

AF:

0.00

AC:

AN:

15752

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

18432

East Asian (EAS)

AF:

0.00

AC:

AN:

26574

South Asian (SAS)

AF:

0.00

AC:

AN:

52670

European-Finnish (FIN)

AF:

0.00

AC:

AN:

28484

Middle Eastern (MID)

AF:

0.00

AC:

AN:

3454

European-Non Finnish (NFE)

AF:

0.0000171

AC:

AN:

991804

Other (OTH)

AF:

0.00

AC:

AN:

49432

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.507

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000756

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

PhyloP100

-0.65

Mutation Taster

=77/23

polymorphism

(source)

Splicing

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over