rs281865036

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PVS1_ModeratePM2PP5

The NM_024312.5(GNPTAB):​c.3434+1G>A variant causes a splice donor, intron change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000747 in 1,338,590 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 Pathogenic (no stars).

Frequency

Genomes: not found (cov: 33)
Exomes 𝑓: 7.5e-7 ( 0 hom. )

Consequence

GNPTAB
NM_024312.5 splice_donor, intron

Scores

5
1
1
Splicing: ADA: 1.000
2

Clinical Significance

Pathogenic no assertion criteria provided P:1

Conservation

PhyloP100: 7.57
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 made for transcript

Verdict is Uncertain_significance. Variant got 5 ACMG points.

PVS1
Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.026252983 fraction of the gene. No cryptic splice site detected. Exon removal is inframe change.
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 12-101757211-C-T is Pathogenic according to our data. Variant chr12-101757211-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 38426.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr12-101757211-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
GNPTABNM_024312.5 linkc.3434+1G>A splice_donor_variant, intron_variant Intron 18 of 20 ENST00000299314.12 NP_077288.2 Q3T906-1
GNPTABXM_011538731.3 linkc.3353+1G>A splice_donor_variant, intron_variant Intron 18 of 20 XP_011537033.1
GNPTABXM_006719593.4 linkc.3434+1G>A splice_donor_variant, intron_variant Intron 18 of 18 XP_006719656.1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
GNPTABENST00000299314.12 linkc.3434+1G>A splice_donor_variant, intron_variant Intron 18 of 20 1 NM_024312.5 ENSP00000299314.7 Q3T906-1
GNPTABENST00000550718.1 linkc.245+1G>A splice_donor_variant, intron_variant Intron 3 of 3 3 ENSP00000449557.1 H0YIK3
GNPTABENST00000549194.1 linkn.301G>A non_coding_transcript_exon_variant Exon 3 of 3 3
GNPTABENST00000549738.5 linkn.185+1G>A splice_donor_variant, intron_variant Intron 2 of 4 4 ENSP00000450161.1 H0YIU2

Frequencies

GnomAD3 genomes
Cov.:
33
GnomAD4 exome
AF:
7.47e-7
AC:
1
AN:
1338590
Hom.:
0
Cov.:
21
AF XY:
0.00000149
AC XY:
1
AN XY:
672404
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.0000120
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
33

ClinVar

Significance: Pathogenic
Submissions summary: Pathogenic:1
Revision: no assertion criteria provided
LINK: link

Submissions by phenotype

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
0.39
CADD
Pathogenic
31
DANN
Uncertain
0.99
Eigen
Pathogenic
1.2
Eigen_PC
Pathogenic
1.0
FATHMM_MKL
Pathogenic
0.98
D
GERP RS
5.9

Splicing

Name
Calibrated prediction
Score
Prediction
dbscSNV1_ADA
Pathogenic
1.0
dbscSNV1_RF
Pathogenic
0.94
SpliceAI score (max)
0.99
Details are displayed if max score is > 0.2
DS_DL_spliceai
0.99
Position offset: 1

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: rs281865036; hg19: chr12-102150989; API