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rs281865017

chr12-101757217-G-GT

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1PM2PP5_Moderate

The NM_024312.5(GNPTAB):c.3428_3429insA(p.Asn1143LysfsTer3) variant causes a frameshift change. The variant allele was found at a frequency of 0.0000043 in 1,396,862 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★). Synonymous variant affecting the same amino acid position (i.e. N1143N) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: not found (cov: 33)
Exomes 𝑓: 0.0000043 ( 0 hom. )

Consequence

GNPTAB
NM_024312.5 frameshift

Scores

Not classified

Clinical Significance

Pathogenic criteria provided, single submitter P:1O:1

Conservation

PhyloP100: 4.77
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 12 ACMG points.

PVS1
?
    PVS1 - null variant (nonsense, frameshift, canonical ±1 or 2 splice sites, initiation codon, single or multiexon deletion) in a gene where LOF is a known mechanism of disease
Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
PM2
?
    PM2 - Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium
Very rare variant in population databases, with high coverage;
PP5
?
    PP5 - Reputable source recently reports variant as pathogenic, but the evidence is not available to the laboratory to perform an independent evaluation
Variant 12-101757217-G-GT is Pathogenic according to our data. Variant chr12-101757217-G-GT is described in ClinVar as [Pathogenic]. Clinvar id is 39072.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
GNPTABNM_024312.5 linkuse as main transcriptc.3428_3429insA p.Asn1143LysfsTer3 frameshift_variant 18/21 ENST00000299314.12
GNPTABXM_006719593.4 linkuse as main transcriptc.3428_3429insA p.Asn1143LysfsTer3 frameshift_variant 18/19
GNPTABXM_011538731.3 linkuse as main transcriptc.3347_3348insA p.Asn1116LysfsTer3 frameshift_variant 18/21

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
GNPTABENST00000299314.12 linkuse as main transcriptc.3428_3429insA p.Asn1143LysfsTer3 frameshift_variant 18/211 NM_024312.5 P1Q3T906-1
GNPTABENST00000550718.1 linkuse as main transcriptc.240_241insA p.Asn81LysfsTer3 frameshift_variant 3/43
GNPTABENST00000549194.1 linkuse as main transcriptn.294_295insA non_coding_transcript_exon_variant 3/33
GNPTABENST00000549738.5 linkuse as main transcriptc.179_180insA p.Asn60LysfsTer3 frameshift_variant, NMD_transcript_variant 2/54

Frequencies

GnomAD3 genomes
?
    Genome Aggregation Database, over 76,156 genomes
Cov.:
33
GnomAD4 exome
AF:
0.00000430
AC:
6
AN:
1396862
Hom.:
0
Cov.:
25
AF XY:
0.00000429
AC XY:
3
AN XY:
698644
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.000127
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
9.49e-7
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
?
    Genome Aggregation Database, over 76,156 genomes
Cov.:
33

ClinVar

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

Submissions by phenotype

Pseudo-Hurler polydystrophy;C2673377:Mucolipidosis type II Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingInvitaeNov 10, 2021This sequence change creates a premature translational stop signal (p.Asn1143Lysfs*3) in the GNPTAB gene. It is expected to result in an absent or disrupted protein product. 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). This premature translational stop signal has been observed in individual(s) with mucolipidosis II (PMID: 19197337). This variant is also known as c.3428_3429insA. ClinVar contains an entry for this variant (Variation ID: 39072). For these reasons, this variant has been classified as Pathogenic. -
Mucolipidosis type II Other:1
not provided, no classification providedliterature onlyGeneReviews-- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction

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: rs281865017; hg19: chr12-102150995; API