16-1351972-G-C

Variant names:

• chr16-1351972-G-C
• rs914207699
• NM_032520.5:c.7G>C

Variant summary

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

The NM_032520.5(GNPTG):​c.7G>C​(p.Ala3Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000858 in 1,165,384 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A3T) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 8.6e-7 (0 hom.)
• Consequence: GNPTG NM_032520.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.82
• Publications: 0 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 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GNPTG	NM_032520.5	MANE Select	c.7G>C	p.Ala3Pro	missense	Exon 1 of 11	NP_115909.1
	TSR3	NM_001001410.3	MANE Select	c.-168C>G		upstream_gene	N/A	NP_001001410.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GNPTG	ENST00000204679.9	TSL:1 MANE Select	c.7G>C	p.Ala3Pro	missense	Exon 1 of 11	ENSP00000204679.4
	GNPTG	ENST00000529110.2	TSL:2	c.7G>C	p.Ala3Pro	missense	Exon 1 of 10	ENSP00000435349.2
	GNPTG	ENST00000683887.1		c.7G>C	p.Ala3Pro	missense	Exon 1 of 11	ENSP00000506886.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 8.58e-7 AC: 1 AN: 1165384 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 564232

African (AFR) AF: 0.00 AC: 0 AN: 23494

American (AMR) AF: 0.00 AC: 0 AN: 11470

Ashkenazi Jewish (ASJ) AF: 0.0000600 AC: 1 AN: 16676

East Asian (EAS) AF: 0.00 AC: 0 AN: 26294

South Asian (SAS) AF: 0.00 AC: 0 AN: 40718

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 26054

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3254

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 970074

Other (OTH) AF: 0.00 AC: 0 AN: 47350

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Uncertain	0.12	D
BayesDel_noAF	Uncertain	-0.070
CADD	Benign	20
DANN	Benign	0.93
DEOGEN2	Benign	0.15	T
Eigen	Benign	-0.073
Eigen_PC	Benign	-0.11
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Benign	0.33	T
M_CAP	Pathogenic	0.97	D
MetaRNN	Uncertain	0.57	D
MetaSVM	Benign	-0.39	T
MutationAssessor	Benign	1.7	L
PhyloP100		2.8
PrimateAI	Uncertain	0.69	T
PROVEAN	Benign	-0.22	N
REVEL	Benign	0.23
Sift	Benign	0.15	T
Sift4G	Uncertain	0.059	T
Polyphen		0.84	P
Vest4		0.46
MutPred		0.34		Loss of helix (P = 0.0033)
MVP		0.96
MPC		0.0062
ClinPred		0.28	T
GERP RS		2.6
PromoterAI		-0.080	Neutral
Varity_R		0.25
gMVP		0.73

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

Other links and lift over

dbSNP: rs914207699; hg19: chr16-1401973;