rs193302849

Positions:

• chr16-1362061-CCAA-C

Variant summary

Our verdict is Pathogenic. Variant got 13 ACMG points: 13P and 0B. PM1 PM2 PM4_Supporting PP5_Very_Strong

The NM_032520.5(GNPTG):​c.347_349del​(p.Asn116del) variant causes a inframe deletion change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000502 in 1,612,434 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. A114A) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.000059 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000049 (0 hom.)
• Consequence: GNPTG NM_032520.5 inframe_deletion
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:7 O:1
• Conservation: PhyloP100: 8.60

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 13 ACMG points.

• PM1: In a domain MRH (size 102) in uniprot entity GNPTG_HUMAN there are 17 pathogenic changes around while only 5 benign (77%) in NM_032520.5
• PM2: Very rare variant in population databases, with high coverage
• PM4: Nonframeshift variant in NON repetitive region in NM_032520.5. Strenght limited to Supporting due to length of the change: 1aa.
• PP5: Variant 16-1362061-CCAA-C is Pathogenic according to our data. Variant chr16-1362061-CCAA-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 21715.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-1362061-CCAA-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GNPTG	NM_032520.5	c.347_349del	p.Asn116del	inframe_deletion	6/11	ENST00000204679.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GNPTG	ENST00000204679.9	c.347_349del	p.Asn116del	inframe_deletion	6/11	1	NM_032520.5	P1

Frequencies

GnomAD3 genomes AF: 0.0000591 AC: 9 AN: 152238 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000965

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

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: 0.0000588

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000929 AC: 23 AN: 247476 Hom.: 0 AF XY: 0.0000744 AC XY: 10 AN XY: 134420

Gnomad AFR exome AF: 0.0000633

Gnomad AMR exome AF: 0.000233

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000117

Gnomad OTH exome AF: 0.000166

GnomAD4 exome AF: 0.0000493 AC: 72 AN: 1460196 Hom.: 0 AF XY: 0.0000509 AC XY: 37 AN XY: 726402

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.000179

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.0000380

Gnomad4 NFE exome AF: 0.0000504

Gnomad4 OTH exome AF: 0.0000497

GnomAD4 genome AF: 0.0000591 AC: 9 AN: 152238 Hom.: 0 Cov.: 33 AF XY: 0.0000269 AC XY: 2 AN XY: 74382

Gnomad4 AFR AF: 0.0000965

Gnomad4 AMR AF: 0.0000654

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000588

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000540 Hom.: 0

Bravo AF: 0.0000567

EpiCase AF: 0.000164

EpiControl AF: 0.0000595

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:7 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

GNPTG-mucolipidosis Pathogenic:4 Other:1

Pathogenic, criteria provided, single submitter	research	Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center	Mar 25, 2024	- -
not provided, no classification provided	literature only	GeneReviews	-	- -
Pathogenic, criteria provided, single submitter	curation	Laboratory of Medical Genetics, National & Kapodistrian University of Athens	Feb 01, 2024	- -
Pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Nov 23, 2020	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Mar 30, 2022	- -

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Apr 01, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jan 14, 2024	This variant, c.347_349del, results in the deletion of 1 amino acid(s) of the GNPTG protein (p.Asn116del), but otherwise preserves the integrity of the reading frame. This variant is present in population databases (rs774681948, gnomAD 0.02%). This variant has been observed in individuals with mucolipidosis type III (PMID: 15532026, 19370764, 29170090). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 21715). Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. Experimental studies have shown that this variant affects GNPTG function (PMID: 15532026). For these reasons, this variant has been classified as Pathogenic. -

Rod-cone dystrophy Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Clinical Genetics and Genomics, Karolinska University Hospital

Jan 31, 2023

- -

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: rs193302849; hg19: chr16-1412062;