rs34946266
Variant summary
Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM1PM2PP5_Very_Strong
The NM_024312.5(GNPTAB):c.569A>T(p.Asp190Val) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000623 in 1,604,824 control chromosomes in the GnomAD database, with no homozygous occurrence. 2/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D190G) has been classified as Uncertain significance.
Frequency
Consequence
NM_024312.5 missense, splice_region
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 12 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
GNPTAB | NM_024312.5 | c.569A>T | p.Asp190Val | missense_variant, splice_region_variant | 5/21 | ENST00000299314.12 | |
GNPTAB | XM_011538731.3 | c.488A>T | p.Asp163Val | missense_variant, splice_region_variant | 5/21 | ||
GNPTAB | XM_006719593.4 | c.569A>T | p.Asp190Val | missense_variant, splice_region_variant | 5/19 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
GNPTAB | ENST00000299314.12 | c.569A>T | p.Asp190Val | missense_variant, splice_region_variant | 5/21 | 1 | NM_024312.5 | P1 | |
GNPTAB | ENST00000549940.5 | c.569A>T | p.Asp190Val | missense_variant, splice_region_variant | 5/11 | 1 | |||
GNPTAB | ENST00000552681.1 | c.203A>T | p.Asp68Val | missense_variant, splice_region_variant | 1/3 | 1 | |||
GNPTAB | ENST00000550352.1 | n.363A>T | non_coding_transcript_exon_variant | 3/3 | 3 |
Frequencies
GnomAD3 genomes ? AF: 0.00000657 AC: 1AN: 152206Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.00000398 AC: 1AN: 251058Hom.: 0 AF XY: 0.00000737 AC XY: 1AN XY: 135718
GnomAD4 exome AF: 0.00000620 AC: 9AN: 1452618Hom.: 0 Cov.: 29 AF XY: 0.00000553 AC XY: 4AN XY: 723364
GnomAD4 genome ? AF: 0.00000657 AC: 1AN: 152206Hom.: 0 Cov.: 32 AF XY: 0.0000134 AC XY: 1AN XY: 74354
ClinVar
Submissions by phenotype
Mucolipidosis type II Pathogenic:1Uncertain:1
Uncertain significance, no assertion criteria provided | clinical testing | Natera, Inc. | Aug 20, 2020 | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Laboratory of Medical Genetics, National & Kapodistrian University of Athens | Oct 01, 2021 | PM2, PP2, PP3, PP4, PP5 - |
Pseudo-Hurler polydystrophy;C2673377:Mucolipidosis type II Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Oct 03, 2023 | This sequence change replaces aspartic acid, which is acidic and polar, with valine, which is neutral and non-polar, at codon 190 of the GNPTAB protein (p.Asp190Val). This variant is present in population databases (rs34946266, gnomAD 0.0009%). This missense change has been observed in individual(s) with mucolipidoses (PMID: 16465621, 19617216). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 38431). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be tolerated. Experimental studies have shown that this missense change does not substantially affect GNPTAB function (PMID: 16465621, 19617216). 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. - |
Mucopolysaccharidosis, MPS-III-A Pathogenic:1
Pathogenic, no assertion criteria provided | curation | GeneReviews | May 10, 2012 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at