16-1362287-AC-ACC

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_032520.5(GNPTG):c.499dup(p.Leu167ProfsTer32) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000211 in 1,612,884 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. T165T) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: 𝑓 0.000033 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000020 (0 hom.)
• Consequence: GNPTG NM_032520.5 frameshift
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:8
• Conservation: PhyloP100: 7.36

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]

ACMG classification

Verdict is Pathogenic. Variant got 18 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 16-1362287-A-AC is Pathogenic according to our data. Variant chr16-1362287-A-AC is described in ClinVar as [Pathogenic]. Clinvar id is 437454.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GNPTG	NM_032520.5	c.499dup	p.Leu167ProfsTer32	frameshift_variant	7/11	ENST00000204679.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GNPTG	ENST00000204679.9	c.499dup	p.Leu167ProfsTer32	frameshift_variant	7/11	1	NM_032520.5	P1

Frequencies

GnomAD3 genomes AF: 0.0000329 AC: 5 AN: 151942 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000484

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000441

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000441 AC: 11 AN: 249592 Hom.: 0 AF XY: 0.0000591 AC XY: 8 AN XY: 135324

Gnomad AFR exome AF: 0.000125

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000710

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000199 AC: 29 AN: 1460942 Hom.: 0 Cov.: 33 AF XY: 0.0000220 AC XY: 16 AN XY: 726826

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000232

Gnomad4 FIN exome AF: 0.0000380

Gnomad4 NFE exome AF: 0.0000180

Gnomad4 OTH exome AF: 0.0000497

GnomAD4 genome AF: 0.0000329 AC: 5 AN: 151942 Hom.: 0 Cov.: 33 AF XY: 0.0000270 AC XY: 2 AN XY: 74200

Gnomad4 AFR AF: 0.0000484

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000441

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000109 Hom.: 0

Bravo AF: 0.0000378

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

GNPTG-mucolipidosis Pathogenic:7

Pathogenic, no assertion criteria provided	literature only	OMIM	Mar 01, 2000	- -
Pathogenic, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 22, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Mar 21, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	Counsyl	Aug 01, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	Genomic Research Center, Shahid Beheshti University of Medical Sciences	Jun 18, 2017	- -
Pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	Neuberg Centre For Genomic Medicine, NCGM	-	The frame shift c.499dupC (p.Leu167Profs32) variant has been reported previously in homozygous state in several individuals affected with mucolipidosis III (Tüysüz B et al.,2017). The p.L167Pfs32 variant is observed in (0.0125%) alleles from individuals of African background in gnomAD Exomes and is novel (not in any individuals) in 1000 Genomes. This variant has been reported to ClinVar database as Pathogenic. This variant is predicted to cause loss of normal protein function through protein truncation. Loss of function variants have been previously reported to be disease causing. For these reasons, this variant has been classified as Pathogenic. -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Sep 08, 2023

This sequence change creates a premature translational stop signal (p.Leu167Profs*32) in the GNPTG gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in GNPTG are known to be pathogenic (PMID: 19370764, 20301784). This variant is present in population databases (rs756959430, gnomAD 0.008%). This premature translational stop signal has been observed in individuals with mucolipidosis III (PMID: 29170090). ClinVar contains an entry for this variant (Variation ID: 437454). For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

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

Publications

LitVar

Other links and lift over

dbSNP: rs756959430; hg19: chr16-1412288;