rs281865023

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong

The NM_024312.5(GNPTAB):​c.118-2A>G variant causes a splice acceptor, intron change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★★).

Frequency

Genomes: not found (cov: 32)
Exomes 𝑓: 0.0 ( 0 hom. )
Failed GnomAD Quality Control

Consequence

GNPTAB
NM_024312.5 splice_acceptor, intron

Scores

5
1
1
Splicing: ADA: 1.000
2

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:3

Conservation

PhyloP100: 7.67
Variant links:
Genes affected
GNPTAB (HGNC:29670): (N-acetylglucosamine-1-phosphate transferase subunits alpha and beta) This gene encodes two of three subunit types of the membrane-bound enzyme N-acetylglucosamine-1-phosphotransferase, a heterohexameric complex composed of two alpha, two beta, and two gamma subunits. The encoded protein is proteolytically cleaved at the Lys928-Asp929 bond to yield mature alpha and beta polypeptides while the gamma subunits are the product of a distinct gene (GeneID 84572). In the Golgi apparatus, the heterohexameric complex catalyzes the first step in the synthesis of mannose 6-phosphate recognition markers on certain oligosaccharides of newly synthesized lysosomal enzymes. These recognition markers are essential for appropriate trafficking of lysosomal enzymes. Mutations in this gene have been associated with both mucolipidosis II and mucolipidosis IIIA.[provided by RefSeq, May 2010]

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ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 18 ACMG points.

PVS1
Splicing +-2 bp (donor or acceptor) variant, LoF is a know mechanism of disease, No cryptic splice site detected. Exon removal results in frameshift change.
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 12-101796764-T-C is Pathogenic according to our data. Variant chr12-101796764-T-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 38412.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-101796764-T-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
GNPTABNM_024312.5 linkc.118-2A>G splice_acceptor_variant, intron_variant Intron 1 of 20 ENST00000299314.12 NP_077288.2 Q3T906-1
GNPTABXM_011538731.3 linkc.37-2A>G splice_acceptor_variant, intron_variant Intron 1 of 20 XP_011537033.1
GNPTABXM_006719593.4 linkc.118-2A>G splice_acceptor_variant, intron_variant Intron 1 of 18 XP_006719656.1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
GNPTABENST00000299314.12 linkc.118-2A>G splice_acceptor_variant, intron_variant Intron 1 of 20 1 NM_024312.5 ENSP00000299314.7 Q3T906-1

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
Data not reliable, filtered out with message: AC0
AF:
0.00
AC:
0
AN:
1449812
Hom.:
0
Cov.:
28
AF XY:
0.00
AC XY:
0
AN XY:
722248
Gnomad4 AFR exome
AF:
0.00
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:
0.00
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
32

ClinVar

Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:3
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Pseudo-Hurler polydystrophy;C2673377:Mucolipidosis type II Pathogenic:1
Jan 15, 2025
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This sequence change affects an acceptor splice site in intron 1 of the GNPTAB gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in GNPTAB are known to be pathogenic (PMID: 19617216, 25107912). This variant is not present in population databases (gnomAD no frequency). Disruption of this splice site has been observed in individuals with clincial features of mucolipidosis II (PMID: 16630736, 27662472). ClinVar contains an entry for this variant (Variation ID: 38412). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. -

not provided Pathogenic:1
Nov 17, 2021
Revvity Omics, Revvity
Significance: Likely pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Mucolipidosis type II Pathogenic:1
May 10, 2012
GeneReviews
Significance: Pathogenic
Review Status: no assertion criteria provided
Collection Method: curation

- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
0.63
D
BayesDel_noAF
Pathogenic
0.23
CADD
Pathogenic
29
DANN
Uncertain
0.99
Eigen
Pathogenic
1.1
Eigen_PC
Pathogenic
0.93
FATHMM_MKL
Pathogenic
0.98
D
GERP RS
5.8
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.2

Splicing

Name
Calibrated prediction
Score
Prediction
dbscSNV1_ADA
Pathogenic
1.0
dbscSNV1_RF
Pathogenic
0.93
SpliceAI score (max)
0.99
Details are displayed if max score is > 0.2
DS_AL_spliceai
0.99
Position offset: -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.

Other links and lift over

dbSNP: rs281865023; hg19: chr12-102190542; API