16-1351972-G-C

Variant names:

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

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PM5

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 Likely pathogenic.

• 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

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 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr16-1351972-G-A is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GNPTG	NM_032520.5	c.7G>C	p.Ala3Pro	missense_variant	Exon 1 of 11	ENST00000204679.9	NP_115909.1
TSR3	NM_001001410.3	c.-168C>G		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.7G>C	p.Ala3Pro	missense_variant	Exon 1 of 11	1	NM_032520.5	ENSP00000204679.4
TSR3	ENST00000007390.3	c.-168C>G		upstream_gene_variant		1	NM_001001410.3	ENSP00000007390.2

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

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.0000600

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

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

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;T
M_CAP	Pathogenic	0.97	D
MetaRNN	Uncertain	0.57	D;D
MetaSVM	Benign	-0.39	T
MutationAssessor	Benign	1.7	L;.
PrimateAI	Uncertain	0.69	T
PROVEAN	Benign	-0.22	N;.
REVEL	Benign	0.23
Sift	Benign	0.15	T;.
Sift4G	Uncertain	0.059	T;T
Polyphen		0.84	P;.
Vest4		0.46
MutPred		0.34		Loss of helix (P = 0.0033);Loss of helix (P = 0.0033);
MVP		0.96
MPC		0.0062
ClinPred		0.28	T
GERP RS		2.6
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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr16-1401973;