rs281865019

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2PP3_ModeratePP5_Moderate

The NM_024312.5(GNPTAB):​c.3458A>G​(p.Asn1153Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,712 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★). Synonymous variant affecting the same amino acid position (i.e. N1153N) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 33)
Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

GNPTAB
NM_024312.5 missense

Scores

5
12
2

Clinical Significance

Likely pathogenic criteria provided, single submitter P:1O:1

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]

Genome browser will be placed here

ACMG classification

Classification was made for transcript

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

PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.918
PP5
Variant 12-101753516-T-C is Pathogenic according to our data. Variant chr12-101753516-T-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 39075.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr12-101753516-T-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
GNPTABNM_024312.5 linkc.3458A>G p.Asn1153Ser missense_variant Exon 19 of 21 ENST00000299314.12 NP_077288.2 Q3T906-1
GNPTABXM_011538731.3 linkc.3377A>G p.Asn1126Ser missense_variant Exon 19 of 21 XP_011537033.1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
GNPTABENST00000299314.12 linkc.3458A>G p.Asn1153Ser missense_variant Exon 19 of 21 1 NM_024312.5 ENSP00000299314.7 Q3T906-1
GNPTABENST00000549738.5 linkn.*65A>G non_coding_transcript_exon_variant Exon 4 of 5 4 ENSP00000450161.1 H0YIU2
GNPTABENST00000549738.5 linkn.*65A>G 3_prime_UTR_variant Exon 4 of 5 4 ENSP00000450161.1 H0YIU2

Frequencies

GnomAD3 genomes
Cov.:
33
GnomAD4 exome
AF:
6.84e-7
AC:
1
AN:
1461712
Hom.:
0
Cov.:
31
AF XY:
0.00000138
AC XY:
1
AN XY:
727180
show subpopulations
Gnomad4 AFR exome
AF:
0.00
AC:
0
AN:
33476
Gnomad4 AMR exome
AF:
0.00
AC:
0
AN:
44720
Gnomad4 ASJ exome
AF:
0.00
AC:
0
AN:
26132
Gnomad4 EAS exome
AF:
0.00
AC:
0
AN:
39676
Gnomad4 SAS exome
AF:
0.00
AC:
0
AN:
86254
Gnomad4 FIN exome
AF:
0.00
AC:
0
AN:
53420
Gnomad4 NFE exome
AF:
8.99e-7
AC:
1
AN:
1111874
Gnomad4 Remaining exome
AF:
0.00
AC:
0
AN:
60394
Heterozygous variant carriers
0
0
1
1
2
2
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance
GnomAD4 genome
Cov.:
33
Alfa
AF:
0.00
Hom.:
0

ClinVar

Significance: Likely pathogenic
Submissions summary: Pathogenic:1Other:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

Mucolipidosis Pathogenic:1
May 13, 2025
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Significance:Likely pathogenic
Review Status:criteria provided, single submitter
Collection Method:clinical testing

Variant summary: GNPTAB c.3458A>G (p.Asn1153Ser) results in a conservative amino acid change in the encoded protein sequence. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change. The variant was absent in 251162 control chromosomes. c.3458A>G has been observed in a compound heterozygous individual affected with Mucolipidosis (Otomo_2009). At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in about 2% of normal activity in an in vitro assay (Qian_2015). The following publications have been ascertained in the context of this evaluation (PMID: 19197337, 25505245). ClinVar contains an entry for this variant (Variation ID: 39075). Based on the evidence outlined above, the variant was classified as likely pathogenic. -

Pseudo-Hurler polydystrophy Other:1
-
GeneReviews
Significance:not provided
Review Status:no classification provided
Collection Method:literature only

- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.72
BayesDel_addAF
Uncertain
0.063
T
BayesDel_noAF
Benign
-0.15
CADD
Uncertain
24
DANN
Uncertain
1.0
DEOGEN2
Pathogenic
0.89
D
Eigen
Uncertain
0.68
Eigen_PC
Uncertain
0.63
FATHMM_MKL
Pathogenic
0.97
D
LIST_S2
Uncertain
0.97
D
M_CAP
Uncertain
0.17
D
MetaRNN
Pathogenic
0.92
D
MetaSVM
Uncertain
0.44
D
MutationAssessor
Uncertain
2.1
M
PrimateAI
Uncertain
0.71
T
PROVEAN
Uncertain
-3.4
D
REVEL
Pathogenic
0.74
Sift
Uncertain
0.0080
D
Sift4G
Uncertain
0.012
D
Polyphen
1.0
D
Vest4
0.72
MutPred
0.78
Loss of stability (P = 0.0633);
MVP
0.86
MPC
0.73
ClinPred
0.96
D
GERP RS
4.3
Varity_R
0.26
gMVP
0.75
Mutation Taster
=27/73
disease causing (ClinVar)

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.

Other links and lift over

dbSNP: rs281865019; hg19: chr12-102147294; API