16-1351973-C-T

Position:

chr16-1351973-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 4P and 2B. PM2PM5BP4_Moderate

The NM_032520.5(GNPTG):c.8C>T(p.Ala3Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000865 in 1,317,908 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 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. A3T) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00030 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000059 ( 1 hom. )

Consequence

GNPTG
NM_032520.5 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: -0.484

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 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr16-1351972-G-A is described in Lovd as [Likely_pathogenic].

BP4

Computational evidence support a benign effect (MetaRNN=0.14880434).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GNPTG	NM_032520.5 linkuse as main transcript	c.8C>T	p.Ala3Val	missense_variant	1/11	ENST00000204679.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GNPTG	ENST00000204679.9 linkuse as main transcript	c.8C>T	p.Ala3Val	missense_variant	1/11	1	NM_032520.5	P1

Frequencies

GnomAD3 genomes

AF:

0.000237

AC:

AN:

151602

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000749

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000132

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:

0.0000442

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.0000592

AC:

AN:

1166198

Hom.:

Cov.:

AF XY:

0.0000549

AC XY:

AN XY:

564636

show subpopulations

Gnomad4 AFR exome

AF:

0.000765

Gnomad4 AMR exome

AF:

0.0000855

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.0000383

Gnomad4 NFE exome

AF:

0.0000392

Gnomad4 OTH exome

AF:

0.000148

GnomAD4 genome

AF:

0.000297

AC:

AN:

151710

Hom.:

Cov.:

AF XY:

0.000324

AC XY:

AN XY:

74170

show subpopulations

Gnomad4 AFR

AF:

0.000964

Gnomad4 AMR

AF:

0.000131

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000442

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000108

Hom.:

Bravo

AF:

0.000329

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

GNPTG-mucolipidosis

Uncertain:3

Uncertain significance, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Nov 07, 2021	- -
Uncertain significance, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Oct 18, 2022

This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 3 of the GNPTG protein (p.Ala3Val). 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 missense change has been observed in individual(s) with non-syndromic stuttering (PMID: 26130485). ClinVar contains an entry for this variant (Variation ID: 658914). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Not Available"; Align-GVGD: "Class C0". The valine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect 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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.20

BayesDel_addAF

Benign

-0.30

BayesDel_noAF

Benign

-0.27

CADD

Benign

DANN

Benign

0.97

DEOGEN2

Benign

0.17

T;.

Eigen

Benign

-1.1

Eigen_PC

Benign

-1.2

FATHMM_MKL

Benign

0.58

LIST_S2

Benign

0.35

T;T

M_CAP

Pathogenic

0.96

MetaRNN

Benign

0.15

T;T

MetaSVM

Benign

-0.66

MutationAssessor

Benign

1.4

L;.

MutationTaster

Benign

1.0

PrimateAI

Uncertain

0.68

PROVEAN

Benign

-0.43

N;.

REVEL

Benign

0.18

Sift

Benign

0.17

T;.

Sift4G

Benign

0.17

T;T

Polyphen

0.013

B;.

Vest4

0.12

MutPred

0.30

Loss of disorder (P = 0.0272);Loss of disorder (P = 0.0272);

MVP

0.68

MPC

0.0067

ClinPred

0.092

GERP RS

-2.9

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

2.0

Varity_R

0.043

gMVP

0.64

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