rs137853826

Positions:

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 4P and 1B. PM2PM5BP4

The ENST00000204679.9(GNPTG):c.74C>A(p.Ala25Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000221 in 1,581,770 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 (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A25G) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000053 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000019 ( 0 hom. )

Consequence

GNPTG
ENST00000204679.9 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:5O:1

Conservation

PhyloP100: 0.926

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr16-1352123-C-G is described in Lovd as [Likely_pathogenic].

BP4

Computational evidence support a benign effect (MetaRNN=0.34636426).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GNPTG	NM_032520.5 linkuse as main transcript	c.74C>A	p.Ala25Glu	missense_variant	2/11	ENST00000204679.9	NP_115909.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GNPTG	ENST00000204679.9 linkuse as main transcript	c.74C>A	p.Ala25Glu	missense_variant	2/11	1	NM_032520.5	ENSP00000204679	P1

Frequencies

GnomAD3 genomes

AF:

0.0000526

AC:

AN:

152112

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000724

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

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:

0.0000735

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000260

AC:

AN:

192372

Hom.:

AF XY:

0.0000285

AC XY:

AN XY:

105162

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 SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000609

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000189

AC:

AN:

1429658

Hom.:

Cov.:

AF XY:

0.0000226

AC XY:

AN XY:

708340

show subpopulations

Gnomad4 AFR exome

AF:

0.0000304

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000237

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000526

AC:

AN:

152112

Hom.:

Cov.:

AF XY:

0.0000807

AC XY:

AN XY:

74330

show subpopulations

Gnomad4 AFR

AF:

0.0000724

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000735

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000140

Hom.:

Bravo

AF:

0.0000340

ExAC

AF:

0.0000257

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:5Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

GNPTG-mucolipidosis

Uncertain:3

Uncertain significance, criteria provided, single submitter	clinical testing	Counsyl	Mar 08, 2017	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Nov 07, 2021	- -
Uncertain significance, no assertion criteria provided	clinical testing	Natera, Inc.	Feb 18, 2020	- -

not provided

Uncertain:1Other:1

Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Sep 20, 2022	This sequence change replaces alanine, which is neutral and non-polar, with glutamic acid, which is acidic and polar, at codon 25 of the GNPTG protein (p.Ala25Glu). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This variant has not been reported in the literature in individuals affected with GNPTG-related conditions. ClinVar contains an entry for this variant (Variation ID: 68108). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt GNPTG protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -
not provided, no classification provided	literature only	SNPedia	-	- -

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Dec 08, 2023

Variant summary: GNPTG c.74C>A (p.Ala25Glu) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 2.6e-05 in 192372 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.74C>A has been reported in the literature in individuals affected with stuttering with non-informative genotype (example: Kang_2010). This report does not provide unequivocal conclusions about association of the variant with Mucolipidosis III Gamma. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication has been ascertained in the context of this evaluation (PMID: 20147709). Four submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.34

BayesDel_addAF

Uncertain

0.14

BayesDel_noAF

Uncertain

-0.040

CADD

Benign

DANN

Uncertain

0.98

DEOGEN2

Benign

0.21

T;.

Eigen

Benign

-0.47

Eigen_PC

Benign

-0.60

FATHMM_MKL

Uncertain

0.92

LIST_S2

Benign

0.64

T;T

M_CAP

Pathogenic

0.54

MetaRNN

Benign

0.35

T;T

MetaSVM

Benign

-0.99

MutationAssessor

Benign

1.9

M;.

MutationTaster

Benign

1.0

PrimateAI

Pathogenic

0.79

PROVEAN

Benign

-0.75

N;.

REVEL

Uncertain

0.61

Sift

Benign

0.13

T;.

Sift4G

Uncertain

0.0070

D;D

Polyphen

0.45

B;.

Vest4

0.32

MutPred

0.71

Loss of sheet (P = 0.0025);Loss of sheet (P = 0.0025);

MVP

0.92

MPC

0.0064

ClinPred

0.075

GERP RS

-0.68

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.0

Varity_R

0.070

gMVP

0.66

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over