rs193302860

Positions:

• chr16-1363030-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 4P and 2B. PM1 PM2 BP4 BS1_Supporting

The NM_032520.5(GNPTG):​c.857C>T​(p.Thr286Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00014 in 1,614,028 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.00039 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00011 (0 hom.)
• Consequence: GNPTG NM_032520.5 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:5 O:1
• Conservation: PhyloP100: -0.167

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 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM1: In a chain N-acetylglucosamine-1-phosphotransferase subunit gamma (size 280) in uniprot entity GNPTG_HUMAN there are 26 pathogenic changes around while only 5 benign (84%) in NM_032520.5
• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.33453318).
• BS1: Variant frequency is greater than expected in population mid. gnomad4_exome allele frequency = 0.000114 (166/1461824) while in subpopulation MID AF= 0.00225 (13/5768). AF 95% confidence interval is 0.00133. There are 0 homozygotes in gnomad4_exome. There are 90 alleles in male gnomad4_exome subpopulation. Median coverage is 32. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GNPTG	NM_032520.5	c.857C>T	p.Thr286Met	missense_variant	11/11	ENST00000204679.9	NP_115909.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GNPTG	ENST00000204679.9	c.857C>T	p.Thr286Met	missense_variant	11/11	1	NM_032520.5	ENSP00000204679.4

Frequencies

GnomAD3 genomes AF: 0.000388 AC: 59 AN: 152086 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000966

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000524

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000189

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000118

Gnomad OTH AF: 0.000479

GnomAD3 exomes AF: 0.000195 AC: 49 AN: 251280 Hom.: 0 AF XY: 0.000199 AC XY: 27 AN XY: 135828

Gnomad AFR exome AF: 0.000616

Gnomad AMR exome AF: 0.000116

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: 0.000255

Gnomad OTH exome AF: 0.000978

GnomAD4 exome AF: 0.000114 AC: 166 AN: 1461824 Hom.: 0 Cov.: 32 AF XY: 0.000124 AC XY: 90 AN XY: 727214

Gnomad4 AFR exome AF: 0.000478

Gnomad4 AMR exome AF: 0.000268

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.0000562

Gnomad4 NFE exome AF: 0.0000899

Gnomad4 OTH exome AF: 0.000364

GnomAD4 genome AF: 0.000394 AC: 60 AN: 152204 Hom.: 0 Cov.: 33 AF XY: 0.000417 AC XY: 31 AN XY: 74404

Gnomad4 AFR AF: 0.000987

Gnomad4 AMR AF: 0.000523

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000189

Gnomad4 NFE AF: 0.000118

Gnomad4 OTH AF: 0.000474

Alfa AF: 0.000284 Hom.: 0

Bravo AF: 0.000457

ESP6500AA AF: 0.000455 AC: 2

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000272 AC: 33

EpiCase AF: 0.0000545

EpiControl AF: 0.0000593

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:5 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

GNPTG-mucolipidosis Uncertain:3 Other:1

Uncertain significance, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Nov 07, 2021	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -
not provided, no classification provided	literature only	GeneReviews	-	- -
Uncertain significance, no assertion criteria provided	clinical testing	Natera, Inc.	Apr 27, 2017	- -

not provided Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Sep 06, 2022	This sequence change replaces threonine, which is neutral and polar, with methionine, which is neutral and non-polar, at codon 286 of the GNPTG protein (p.Thr286Met). This variant is present in population databases (rs193302860, gnomAD 0.06%). This missense change has been observed in individual(s) with Mucolipidosis III Gamma (PMID: 19370764, 24767253). ClinVar contains an entry for this variant (Variation ID: 21724). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The methionine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. Experimental studies have shown that this missense change does not substantially affect GNPTG function (PMID: 27038293). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -
Uncertain significance, no assertion criteria provided	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Oct 16, 2017	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.070
BayesDel_addAF	Benign	-0.25	T
BayesDel_noAF	Benign	-0.23
CADD	Benign	11
DANN	Benign	0.90
DEOGEN2	Benign	0.16	T
Eigen	Benign	-0.76
Eigen_PC	Benign	-0.95
FATHMM_MKL	Benign	0.062	N
LIST_S2	Benign	0.41	T
M_CAP	Benign	0.085	D
MetaRNN	Benign	0.33	T
MetaSVM	Benign	-0.42	T
MutationAssessor	Benign	1.6	L
PrimateAI	Benign	0.27	T
PROVEAN	Benign	-0.28	N
REVEL	Uncertain	0.34
Sift	Benign	0.23	T
Sift4G	Benign	0.27	T
Polyphen		0.98	D
Vest4		0.086
MVP		0.82
MPC		0.0069
ClinPred		0.0064	T
GERP RS		-1.9
Varity_R		0.0092
gMVP		0.29

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs193302860; hg19: chr16-1413031;