16-1351978-C-A

Variant names:

• chr16-1351978-C-A
• rs543660760
• NM_032520.5:c.13C>A

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_032520.5(GNPTG):​c.13C>A​(p.Leu5Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000146 in 1,371,450 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 8.2e-7 (0 hom.)
• Consequence: GNPTG NM_032520.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -2.75

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 Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.32047766).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GNPTG	NM_032520.5	c.13C>A	p.Leu5Met	missense_variant	Exon 1 of 11	ENST00000204679.9	NP_115909.1
TSR3	NM_001001410.3	c.-174G>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.13C>A	p.Leu5Met	missense_variant	Exon 1 of 11	1	NM_032520.5	ENSP00000204679.4
TSR3	ENST00000007390.3	c.-174G>T		upstream_gene_variant		1	NM_001001410.3	ENSP00000007390.2

Frequencies

GnomAD3 genomes AF: 0.00000659 AC: 1 AN: 151676 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

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: 0.0000147

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 8.20e-7 AC: 1 AN: 1219774 Hom.: 0 Cov.: 32 AF XY: 0.00000168 AC XY: 1 AN XY: 595176

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: 0.00000100

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.00000659 AC: 1 AN: 151676 Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1 AN XY: 74076

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Uncertain	0.014	T
BayesDel_noAF	Benign	-0.22
CADD	Benign	0.26
DANN	Benign	0.76
DEOGEN2	Benign	0.12	T;.
Eigen	Benign	-1.0
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.66	D
LIST_S2	Benign	0.30	T;T
M_CAP	Pathogenic	0.86	D
MetaRNN	Benign	0.32	T;T
MetaSVM	Benign	-0.55	T
MutationAssessor	Benign	0.90	L;.
PrimateAI	Uncertain	0.70	T
PROVEAN	Benign	-0.050	N;.
REVEL	Uncertain	0.35
Sift	Benign	0.11	T;.
Sift4G	Benign	0.19	T;T
Polyphen		0.70	P;.
Vest4		0.18
MutPred		0.35		Gain of disorder (P = 0.0414);Gain of disorder (P = 0.0414);
MVP		0.86
MPC		0.0067
ClinPred		0.34	T
GERP RS		-0.24
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Varity_R		0.11
gMVP		0.57

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: rs543660760; hg19: chr16-1401979;