Genetic Variant GNPTG:p.Met1? (chr16-1351968-G-A) – ACMG Classification: Likely_pathogenic (6 pts)

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PVS1_StrongPM2

The NM_032520.5(GNPTG):c.3G>A(p.Met1?) variant causes a start lost change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

GNPTG
NM_032520.5 start_lost

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.0570

Publications

0 publications found

Variant links:

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]

GNPTG links:

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]

TSR3 links:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

PVS1

Start lost variant, next in-frame start position is after 5 pathogenic variants. Next in-frame start position is after 27 codons. Genomic position: 1352128. Lost 0.086 part of the original CDS.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GNPTG	NM_032520.5	MANE Select	c.3G>A	p.Met1?	start_lost	Exon 1 of 11	NP_115909.1	Q9UJJ9
	TSR3	NM_001001410.3	MANE Select	c.-164C>T		upstream_gene	N/A	NP_001001410.1	Q9UJK0

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
GNPTG	ENST00000204679.9	TSL:1 MANE Select	c.3G>A	p.Met1?	start_lost	Exon 1 of 11	ENSP00000204679.4	Q9UJJ9
GNPTG	ENST00000891792.1		c.3G>A	p.Met1?	start_lost	Exon 1 of 12	ENSP00000561851.1
GNPTG	ENST00000529110.2	TSL:2	c.3G>A	p.Met1?	start_lost	Exon 1 of 10	ENSP00000435349.2	H0YEA7

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

1151232

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

555874

African (AFR)

AF:

0.00

AC:

AN:

23228

American (AMR)

AF:

0.00

AC:

AN:

10468

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

16142

East Asian (EAS)

AF:

0.00

AC:

AN:

26138

South Asian (SAS)

AF:

0.00

AC:

AN:

37106

European-Finnish (FIN)

AF:

0.00

AC:

AN:

25222

Middle Eastern (MID)

AF:

0.00

AC:

AN:

3198

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

963044

Other (OTH)

AF:

0.00

AC:

AN:

46686

GnomAD4 genome

Cov.:

ClinVar

ClinVar submissions as Germline

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.63

BayesDel_noAF

Pathogenic

0.16

CADD

Benign

(source)

DANN

Benign

0.97

DEOGEN2

Benign

0.26

Eigen

Benign

-0.15

Eigen_PC

Benign

-0.16

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.90

M_CAP

Pathogenic

0.99

MetaRNN

Pathogenic

0.98

MetaSVM

Benign

-0.38

PhyloP100

0.057

PROVEAN

Benign

-0.45

REVEL

Uncertain

0.55

Sift

Benign

0.48

Sift4G

Benign

0.10

Polyphen

0.81

Vest4

0.55

MutPred

0.94

Gain of catalytic residue at M1 (P = 0.0084)

MVP

0.93

ClinPred

0.92

GERP RS

2.6

PromoterAI

-0.37

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

2.6

Varity_R

0.40

gMVP

0.68

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over