16-1352123-C-G

Variant names:

• chr16-1352123-C-G
• rs137853826
• NM_032520.5:c.74C>G

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_032520.5(GNPTG):​c.74C>G​(p.Ala25Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. 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. A25E) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: GNPTG NM_032520.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:2
• Conservation: PhyloP100: 0.926
• Publications: 5 publications found

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

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.10080704).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_032520.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GNPTG	NM_032520.5	MANE Select	c.74C>G	p.Ala25Gly	missense	Exon 2 of 11	NP_115909.1	Q9UJJ9
	TSR3	NM_001001410.3	MANE Select	c.-319G>C		upstream_gene	N/A	NP_001001410.1	Q9UJK0

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GNPTG	ENST00000204679.9	TSL:1 MANE Select	c.74C>G	p.Ala25Gly	missense	Exon 2 of 11	ENSP00000204679.4	Q9UJJ9
	GNPTG	ENST00000891792.1		c.74C>G	p.Ala25Gly	missense	Exon 2 of 12	ENSP00000561851.1
	GNPTG	ENST00000529110.2	TSL:2	c.158C>G	p.Ala53Gly	missense	Exon 1 of 10	ENSP00000435349.2	H0YEA7

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1429658 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 708340

African (AFR) AF: 0.00 AC: 0 AN: 32926

American (AMR) AF: 0.00 AC: 0 AN: 39842

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25524

East Asian (EAS) AF: 0.00 AC: 0 AN: 38064

South Asian (SAS) AF: 0.00 AC: 0 AN: 82048

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 49326

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5054

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1097800

Other (OTH) AF: 0.00 AC: 0 AN: 59074

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	GNPTG-mucolipidosis (1)
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.078
BayesDel_addAF	Benign	-0.11	T
BayesDel_noAF	Benign	-0.40
CADD	Benign	16
DANN	Benign	0.81
DEOGEN2	Benign	0.090	T
Eigen	Benign	-0.62
Eigen_PC	Benign	-0.70
FATHMM_MKL	Benign	0.63	D
LIST_S2	Benign	0.57	T
M_CAP	Uncertain	0.24	D
MetaRNN	Benign	0.10	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.42	N
PhyloP100		0.93
PrimateAI	Uncertain	0.77	T
PROVEAN	Benign	0.60	N
REVEL	Benign	0.12
Sift	Benign	0.64	T
Sift4G	Benign	1.0	T
Polyphen		0.0	B
Vest4		0.083
MutPred		0.20		Gain of relative solvent accessibility (P = 0.0023)
MVP		0.82
MPC		0.0067
ClinPred		0.054	T
GERP RS		-0.68
PromoterAI		0.028	Neutral
Varity_R		0.024
gMVP		0.52

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.080		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs137853826; hg19: chr16-1402124;