16-1351956-C-A

Variant names:

• chr16-1351956-C-A
• rs1017797000
• NM_032520.5:c.-10C>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BS1 BS2

The NM_032520.5(GNPTG):​c.-10C>A variant causes a 5 prime UTR premature start codon gain change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.001 in 1,291,514 control chromosomes in the GnomAD database, including 5 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00052 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0011 (5 hom.)
• Consequence: GNPTG NM_032520.5 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Uncertain significance criteria provided, single submitter U:2 B:1
• Conservation: PhyloP100: 0.588
• 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: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.58).
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.000521 (79/151746) while in subpopulation NFE AF = 0.000958 (65/67880). AF 95% confidence interval is 0.00077. There are 0 homozygotes in GnomAd4. There are 33 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 5 AR gene

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.-10C>A		5_prime_UTR_premature_start_codon_gain	Exon 1 of 11	NP_115909.1	Q9UJJ9
	GNPTG	NM_032520.5	MANE Select	c.-10C>A		5_prime_UTR	Exon 1 of 11	NP_115909.1	Q9UJJ9
	TSR3	NM_001001410.3	MANE Select	c.-152G>T		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.-10C>A		5_prime_UTR_premature_start_codon_gain	Exon 1 of 11	ENSP00000204679.4	Q9UJJ9
	GNPTG	ENST00000204679.9	TSL:1 MANE Select	c.-10C>A		5_prime_UTR	Exon 1 of 11	ENSP00000204679.4	Q9UJJ9
	GNPTG	ENST00000891785.1		c.-10C>A		5_prime_UTR_premature_start_codon_gain	Exon 1 of 11	ENSP00000561844.1

Frequencies

GnomAD3 genomes AF: 0.000521 AC: 79 AN: 151640 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000242

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

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: 0.000957

Gnomad OTH AF: 0.000960

GnomAD2 exomes AF: 0.000722 AC: 8 AN: 11088 AF XY: 0.00113

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00133

Gnomad OTH exome AF: 0.00543

GnomAD4 exome AF: 0.00107 AC: 1215 AN: 1139768 Hom.: 5 Cov.: 32 AF XY: 0.00104 AC XY: 573 AN XY: 549150

African (AFR) AF: 0.0000874 AC: 2 AN: 22896

American (AMR) AF: 0.000210 AC: 2 AN: 9522

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 15278

East Asian (EAS) AF: 0.00 AC: 0 AN: 25836

South Asian (SAS) AF: 0.00 AC: 0 AN: 34786

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 24600

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3122

European-Non Finnish (NFE) AF: 0.00122 AC: 1169 AN: 957586

Other (OTH) AF: 0.000910 AC: 42 AN: 46142

GnomAD4 genome AF: 0.000521 AC: 79 AN: 151746 Hom.: 0 Cov.: 32 AF XY: 0.000445 AC XY: 33 AN XY: 74170

African (AFR) AF: 0.000241 AC: 10 AN: 41448

American (AMR) AF: 0.000131 AC: 2 AN: 15236

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5164

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10414

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 292

European-Non Finnish (NFE) AF: 0.000958 AC: 65 AN: 67880

Other (OTH) AF: 0.000950 AC: 2 AN: 2106

Alfa AF: 0.000832 Hom.: 0

Bravo AF: 0.000446

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	2	-	GNPTG-mucolipidosis (2)
-	-	1	GNPTG-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.58
CADD	Benign	7.4
DANN	Benign	0.87
PhyloP100		0.59
PromoterAI		-0.030	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0

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: rs1017797000; hg19: chr16-1401957;