16-1351968-G-A

Variant names:

• chr16-1351968-G-A
• NM_032520.5:c.3G>A

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PVS1_Strong PM2

The NM_032520.5(GNPTG):​c.3G>A​(p.Met1?) variant causes a start lost change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: GNPTG NM_032520.5 start_lost
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.0570

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]

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]

ACMG classification

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

• PVS1: Start lost variant, next in-frame start position is after 6 pathogenic variants. Next in-frame start position is after 27 codons. Genomic position: 1352128. Lost 0.086 part of the original CDS.
• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GNPTG	NM_032520.5	c.3G>A	p.Met1?	start_lost	Exon 1 of 11	ENST00000204679.9	NP_115909.1
TSR3	NM_001001410.3	c.-164C>T		upstream_gene_variant		ENST00000007390.3	NP_001001410.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GNPTG	ENST00000204679.9	c.3G>A	p.Met1?	start_lost	Exon 1 of 11	1	NM_032520.5	ENSP00000204679.4
TSR3	ENST00000007390.3	c.-164C>T		upstream_gene_variant		1	NM_001001410.3	ENSP00000007390.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1151232 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 555874

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: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Apr 29, 2021

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant has been observed in individual(s) with mucolipidosis type III gamma (Invitae). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate insufficient coverage at this position in the ExAC database. This sequence change affects the initiator methionine of the GNPTG mRNA. The next in-frame methionine is located at codon p.Met27. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. 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
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.16
CADD	Benign	22
DANN	Benign	0.97
DEOGEN2	Benign	0.26	T;.
Eigen	Benign	-0.15
Eigen_PC	Benign	-0.16
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.90	D;D
M_CAP	Pathogenic	0.99	D
MetaRNN	Pathogenic	0.98	D;D
MetaSVM	Benign	-0.38	T
PROVEAN	Benign	-0.45	N;.
REVEL	Uncertain	0.55
Sift	Benign	0.48	T;.
Sift4G	Benign	0.10	T;T
Polyphen		0.81	P;.
Vest4		0.55
MutPred		0.94		Gain of catalytic residue at M1 (P = 0.0084);Gain of catalytic residue at M1 (P = 0.0084);
MVP		0.93
ClinPred		0.92	D
GERP RS		2.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.6
Varity_R		0.40
gMVP		0.68

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr16-1401969;