12-101770477-T-G
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Variant summary
Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2
The NM_024312.5(GNPTAB):c.1042A>C(p.Ile348Leu) variant causes a missense change. The variant allele was found at a frequency of 0.00213 in 1,613,892 control chromosomes in the GnomAD database, including 50 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).
Frequency
Genomes: 𝑓 0.012 ( 24 hom., cov: 32)
Exomes 𝑓: 0.0011 ( 26 hom. )
Consequence
GNPTAB
NM_024312.5 missense
NM_024312.5 missense
Scores
2
10
6
Clinical Significance
Conservation
PhyloP100: 5.84
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 Benign. Variant got -20 ACMG points.
BP4
Computational evidence support a benign effect (MetaRNN=0.009780139).
BP6
Variant 12-101770477-T-G is Benign according to our data. Variant chr12-101770477-T-G is described in ClinVar as [Likely_benign]. Clinvar id is 39020.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-101770477-T-G is described in Lovd as [Pathogenic].
BS1
Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0117 (1781/152316) while in subpopulation AFR AF= 0.0411 (1707/41564). AF 95% confidence interval is 0.0394. There are 24 homozygotes in gnomad4. There are 812 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
BS2
High Homozygotes in GnomAd4 at 24 AR gene
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
GNPTAB | NM_024312.5 | c.1042A>C | p.Ile348Leu | missense_variant | 9/21 | ENST00000299314.12 | NP_077288.2 | |
GNPTAB | XM_011538731.3 | c.961A>C | p.Ile321Leu | missense_variant | 9/21 | XP_011537033.1 | ||
GNPTAB | XM_006719593.4 | c.1042A>C | p.Ile348Leu | missense_variant | 9/19 | XP_006719656.1 |
Ensembl
Frequencies
GnomAD3 genomes AF: 0.0117 AC: 1783AN: 152198Hom.: 24 Cov.: 32
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GnomAD3 exomes AF: 0.00302 AC: 759AN: 251420Hom.: 8 AF XY: 0.00216 AC XY: 293AN XY: 135884
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GnomAD4 exome AF: 0.00113 AC: 1654AN: 1461576Hom.: 26 Cov.: 31 AF XY: 0.000989 AC XY: 719AN XY: 727110
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GnomAD4 genome AF: 0.0117 AC: 1781AN: 152316Hom.: 24 Cov.: 32 AF XY: 0.0109 AC XY: 812AN XY: 74484
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ClinVar
Significance: Benign/Likely benign
Submissions summary: Benign:13Other:1
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not provided Benign:4
Likely benign, criteria provided, single submitter | not provided | Breakthrough Genomics, Breakthrough Genomics | - | - - |
Likely benign, criteria provided, single submitter | clinical testing | Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics | Jan 24, 2017 | - - |
Benign, no assertion criteria provided | clinical testing | Mayo Clinic Laboratories, Mayo Clinic | Sep 27, 2017 | - - |
Likely benign, criteria provided, single submitter | clinical testing | GeneDx | Mar 24, 2019 | This variant is associated with the following publications: (PMID: 27884173, 19617216, 25505245, 22995991) - |
Mucolipidosis type II Benign:3Other:1
not provided, no classification provided | literature only | GeneReviews | - | - - |
Likely benign, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Apr 28, 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. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. - |
Benign, no assertion criteria provided | clinical testing | Natera, Inc. | Jan 09, 2020 | - - |
Likely benign, criteria provided, single submitter | clinical testing | Mendelics | May 28, 2019 | - - |
not specified Benign:3
Benign, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | - | - - |
Benign, criteria provided, single submitter | clinical testing | Al Jalila Children’s Genomics Center, Al Jalila Childrens Speciality Hospital | Mar 25, 2020 | - - |
Likely benign, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Dec 10, 2021 | - - |
Pseudo-Hurler polydystrophy;C2673377:Mucolipidosis type II Benign:2
Likely benign, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Sep 09, 2021 | - - |
Benign, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Feb 01, 2024 | - - |
Pseudo-Hurler polydystrophy Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Apr 28, 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. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Benign
T
BayesDel_noAF
Uncertain
CADD
Pathogenic
DANN
Uncertain
DEOGEN2
Uncertain
D;.
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Pathogenic
D
LIST_S2
Uncertain
D;D
MetaRNN
Benign
T;T
MetaSVM
Uncertain
D
MutationAssessor
Benign
L;L
PrimateAI
Uncertain
T
PROVEAN
Benign
N;N
REVEL
Pathogenic
Sift
Uncertain
D;D
Sift4G
Uncertain
D;T
Polyphen
P;D
Vest4
MVP
MPC
ClinPred
T
GERP RS
Varity_R
gMVP
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at