rs761584357

chr16-1362108-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM1 PM2

The NM_032520.5(GNPTG):c.388C>T(p.Arg130Cys) variant causes a missense change. The variant allele was found at a frequency of 0.0000116 in 1,459,996 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R130H) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.000012 (0 hom.)
• Consequence: GNPTG NM_032520.5 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 6.64

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 Uncertain_significance. Variant got 4 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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GNPTG	NM_032520.5	c.388C>T	p.Arg130Cys	missense_variant	6/11	ENST00000204679.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GNPTG	ENST00000204679.9	c.388C>T	p.Arg130Cys	missense_variant	6/11	1	NM_032520.5	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.0000162 AC: 4 AN: 246192 Hom.: 0 AF XY: 0.0000299 AC XY: 4 AN XY: 133888

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000329

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000271

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000116 AC: 17 AN: 1459996 Hom.: 0 Cov.: 33 AF XY: 0.0000124 AC XY: 9 AN XY: 726270

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: 0.00

Gnomad4 NFE exome AF: 0.0000108

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000378

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

GNPTG-mucolipidosis Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Counsyl

Apr 07, 2017

- -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Sep 17, 2021

This sequence change replaces arginine with cysteine at codon 130 of the GNPTG protein (p.Arg130Cys). The arginine residue is weakly conserved and there is a large physicochemical difference between arginine and cysteine. This variant is present in population databases (rs761584357, ExAC 0.002%). This variant has not been reported in the literature in individuals affected with GNPTG-related conditions. ClinVar contains an entry for this variant (Variation ID: 551401). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.20
BayesDel_addAF	Benign	-0.011	T
BayesDel_noAF	Benign	-0.15
Cadd	Uncertain	25
Dann	Uncertain	0.98
DEOGEN2	Uncertain	0.51	D
Eigen	Benign	-0.33
Eigen_PC	Benign	-0.23
FATHMM_MKL	Uncertain	0.85	D
LIST_S2	Uncertain	0.87	D
M_CAP	Uncertain	0.097	D
MetaRNN	Uncertain	0.43	T
MetaSVM	Benign	-0.57	T
MutationAssessor	Benign	1.0	L
MutationTaster	Benign	0.95	D
PrimateAI	Benign	0.20	T
PROVEAN	Benign	-1.7	N
REVEL	Benign	0.29
Sift	Benign	0.11	T
Sift4G	Uncertain	0.047	D
Polyphen		0.013	B
Vest4		0.41
MutPred		0.49		Loss of MoRF binding (P = 0.0038);
MVP		0.83
MPC		0.0063
ClinPred		0.38	T
GERP RS		3.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.074
gMVP		0.48

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: rs761584357; hg19: chr16-1412109;