chr16-1351976-G-C

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4_StrongBS1_Supporting

The NM_032520.5(GNPTG):c.11G>C(p.Gly4Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000266 in 1,369,452 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G4E) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.000079 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00029 ( 1 hom. )

Consequence

GNPTG
NM_032520.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:4

Conservation

PhyloP100: -0.647

Publications

6 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:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -5 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.056941718).

BS1

Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.0000791 (12/151786) while in subpopulation EAS AF = 0.00232 (12/5162). AF 95% confidence interval is 0.00134. There are 0 homozygotes in GnomAd4. There are 6 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.11G>C	p.Gly4Ala	missense	Exon 1 of 11	NP_115909.1	Q9UJJ9
	TSR3	NM_001001410.3	MANE Select	c.-172C>G		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.11G>C	p.Gly4Ala	missense	Exon 1 of 11	ENSP00000204679.4	Q9UJJ9
GNPTG	ENST00000891792.1		c.11G>C	p.Gly4Ala	missense	Exon 1 of 12	ENSP00000561851.1
GNPTG	ENST00000529110.2	TSL:2	c.11G>C	p.Gly4Ala	missense	Exon 1 of 10	ENSP00000435349.2	H0YEA7

Frequencies

GnomAD3 genomes

AF:

0.0000791

AC:

AN:

151676

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00232

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000266

AC:

AN:

37540

AF XY:

0.0000451

show subpopulations

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:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000289

AC:

352

AN:

1217666

Hom.:

Cov.:

AF XY:

0.000274

AC XY:

163

AN XY:

593928

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

24496

American (AMR)

AF:

0.00

AC:

AN:

16492

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

18688

East Asian (EAS)

AF:

0.0128

AC:

342

AN:

26630

South Asian (SAS)

AF:

0.0000552

AC:

AN:

54322

European-Finnish (FIN)

AF:

0.00

AC:

AN:

28848

Middle Eastern (MID)

AF:

0.00

AC:

AN:

3484

European-Non Finnish (NFE)

AF:

0.00000302

AC:

AN:

995016

Other (OTH)

AF:

0.0000805

AC:

AN:

49690

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.471

Heterozygous variant carriers

115

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0000791

AC:

AN:

151786

Hom.:

Cov.:

AF XY:

0.0000809

AC XY:

AN XY:

74192

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41522

American (AMR)

AF:

0.00

AC:

AN:

15232

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3468

East Asian (EAS)

AF:

0.00232

AC:

AN:

5162

South Asian (SAS)

AF:

0.00

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10434

Middle Eastern (MID)

AF:

0.00

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

67830

Other (OTH)

AF:

0.00

AC:

AN:

2104

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.508

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.0000453

ClinVar

ClinVar submissions as Germline

Significance:Uncertain significance

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

GNPTG-mucolipidosis (3)

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.070

BayesDel_addAF

Benign

-0.21

BayesDel_noAF

Benign

-0.31

CADD

Benign

1.1

(source)

DANN

Benign

0.35

DEOGEN2

Benign

0.11

Eigen

Benign

-1.3

Eigen_PC

Benign

-1.4

FATHMM_MKL

Benign

0.69

LIST_S2

Benign

0.40

M_CAP

Pathogenic

0.55

MetaRNN

Benign

0.057

MetaSVM

Benign

-0.70

MutationAssessor

Benign

-0.060

PhyloP100

-0.65

PrimateAI

Uncertain

0.66

PROVEAN

Benign

-0.26

REVEL

Benign

0.11

Sift

Benign

0.30

Sift4G

Benign

0.29

Polyphen

0.067

Vest4

0.11

MutPred

0.29

Loss of catalytic residue at G4 (P = 0.1135)

MVP

0.64

MPC

0.0065

ClinPred

0.078

GERP RS

1.1

PromoterAI

0.017

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.0

Varity_R

0.028

gMVP

0.52

Mutation Taster

=88/12

polymorphism

(source)

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over