rs112543062
Variant summary
Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2PM5PP3PP5
The NM_024312.5(GNPTAB):āc.1144A>Gā(p.Thr382Ala) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000821 in 1,461,884 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 Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T382P) has been classified as Likely pathogenic.
Frequency
Consequence
NM_024312.5 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_pathogenic. Variant got 6 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
GNPTAB | NM_024312.5 | c.1144A>G | p.Thr382Ala | missense_variant | 10/21 | ENST00000299314.12 | |
GNPTAB | XM_011538731.3 | c.1063A>G | p.Thr355Ala | missense_variant | 10/21 | ||
GNPTAB | XM_006719593.4 | c.1144A>G | p.Thr382Ala | missense_variant | 10/19 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
GNPTAB | ENST00000299314.12 | c.1144A>G | p.Thr382Ala | missense_variant | 10/21 | 1 | NM_024312.5 | P1 | |
GNPTAB | ENST00000549940.5 | c.1144A>G | p.Thr382Ala | missense_variant | 10/11 | 1 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD3 exomes AF: 0.0000119 AC: 3AN: 251434Hom.: 0 AF XY: 0.0000147 AC XY: 2AN XY: 135892
GnomAD4 exome AF: 0.00000821 AC: 12AN: 1461884Hom.: 0 Cov.: 32 AF XY: 0.0000138 AC XY: 10AN XY: 727242
GnomAD4 genome ? Cov.: 32
ClinVar
Submissions by phenotype
Pseudo-Hurler polydystrophy;C2673377:Mucolipidosis type II Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Invitae | Apr 30, 2023 | This variant disrupts the p.Thr382 amino acid residue in GNPTAB. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 30882951, 32651481, 32746448). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt GNPTAB protein function. ClinVar contains an entry for this variant (Variation ID: 1982833). This variant has not been reported in the literature in individuals affected with GNPTAB-related conditions. This variant is present in population databases (rs112543062, gnomAD 0.01%). This sequence change replaces threonine, which is neutral and polar, with alanine, which is neutral and non-polar, at codon 382 of the GNPTAB protein (p.Thr382Ala). - |
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Aug 03, 2023 | Variant summary: GNPTAB c.1144A>G (p.Thr382Ala) results in a non-conservative amino acid change located in the Stealth protein CR2 domain (IPR021520) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 1.2e-05 in 251434 control chromosomes (gnomAD). To our knowledge, no occurrence of c.1144A>G in individuals affected with Mucolipidosis and no experimental evidence demonstrating its impact on protein function have been reported. However, a different missense variant at this codon (p.Thr382Pro) has been classified as disease causing (HGMD:CM1825307, ClinVar:193739), indicating this residue may be clinically significant. One ClinVar submitter has assessed the variant since 2014, and classified the variant as likely pathogenic. Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at