chr16-1351938-G-A

Variant names:

• chr16-1351938-G-A
• rs765220411
• NM_032520.5:c.-28G>A

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4_Strong BS1_Supporting

The NM_032520.5(GNPTG):​c.-28G>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 0.000257 in 1,277,742 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00027 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00025 (0 hom.)
• Consequence: GNPTG NM_032520.5 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.07
• Publications: 1 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: Likely_benign. The variant received -5 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.53).
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00027 (41/151648) while in subpopulation NFE AF = 0.000545 (37/67876). AF 95% confidence interval is 0.000406. There are 0 homozygotes in GnomAd4. There are 15 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

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.-28G>A		5_prime_UTR_premature_start_codon_gain	Exon 1 of 11	NP_115909.1	Q9UJJ9
	GNPTG	NM_032520.5	MANE Select	c.-28G>A		5_prime_UTR	Exon 1 of 11	NP_115909.1	Q9UJJ9
	TSR3	NM_001001410.3	MANE Select	c.-134C>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.-28G>A		5_prime_UTR_premature_start_codon_gain	Exon 1 of 11	ENSP00000204679.4	Q9UJJ9
	GNPTG	ENST00000204679.9	TSL:1 MANE Select	c.-28G>A		5_prime_UTR	Exon 1 of 11	ENSP00000204679.4	Q9UJJ9
	GNPTG	ENST00000891785.1		c.-28G>A		5_prime_UTR_premature_start_codon_gain	Exon 1 of 11	ENSP00000561844.1

Frequencies

GnomAD3 genomes AF: 0.000270 AC: 41 AN: 151648 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00219

Gnomad AMR AF: 0.0000657

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0000961

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000545

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000799 AC: 2 AN: 2502 AF XY: 0.00122

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: 0.00164

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000255 AC: 287 AN: 1126094 Hom.: 0 Cov.: 32 AF XY: 0.000240 AC XY: 130 AN XY: 540816

African (AFR) AF: 0.00 AC: 0 AN: 22656

American (AMR) AF: 0.000120 AC: 1 AN: 8330

Ashkenazi Jewish (ASJ) AF: 0.0000691 AC: 1 AN: 14482

East Asian (EAS) AF: 0.00 AC: 0 AN: 25616

South Asian (SAS) AF: 0.0000316 AC: 1 AN: 31642

European-Finnish (FIN) AF: 0.000126 AC: 3 AN: 23718

Middle Eastern (MID) AF: 0.000328 AC: 1 AN: 3050

European-Non Finnish (NFE) AF: 0.000281 AC: 267 AN: 951236

Other (OTH) AF: 0.000287 AC: 13 AN: 45364

GnomAD4 genome AF: 0.000270 AC: 41 AN: 151648 Hom.: 0 Cov.: 32 AF XY: 0.000203 AC XY: 15 AN XY: 74062

African (AFR) AF: 0.00 AC: 0 AN: 41368

American (AMR) AF: 0.0000657 AC: 1 AN: 15216

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5176

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.0000961 AC: 1 AN: 10408

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 314

European-Non Finnish (NFE) AF: 0.000545 AC: 37 AN: 67876

Other (OTH) AF: 0.00 AC: 0 AN: 2080

Alfa AF: 0.000594 Hom.: 0

Bravo AF: 0.000227

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	GNPTG-mucolipidosis (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.53
CADD	Benign	15
DANN	Benign	0.94
PhyloP100		1.1
PromoterAI		-0.18	Neutral
Mutation Taster		=300/0	polymorphism

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: rs765220411; hg19: chr16-1401939;