rs281864980
Variant summary
Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1PM2PP3_StrongPP5_Very_Strong
The NM_024312.5(GNPTAB):c.1514G>A(p.Cys505Tyr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000929 in 1,614,006 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 Likely pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. C505C) has been classified as Likely benign.
Frequency
Consequence
NM_024312.5 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 16 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
GNPTAB | NM_024312.5 | c.1514G>A | p.Cys505Tyr | missense_variant | 12/21 | ENST00000299314.12 | |
GNPTAB | XM_011538731.3 | c.1433G>A | p.Cys478Tyr | missense_variant | 12/21 | ||
GNPTAB | XM_006719593.4 | c.1514G>A | p.Cys505Tyr | missense_variant | 12/19 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
GNPTAB | ENST00000299314.12 | c.1514G>A | p.Cys505Tyr | missense_variant | 12/21 | 1 | NM_024312.5 | P1 | |
GNPTAB | ENST00000552009.1 | n.173G>A | non_coding_transcript_exon_variant | 2/2 | 3 |
Frequencies
GnomAD3 genomes AF: 0.00000657 AC: 1AN: 152176Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.0000119 AC: 3AN: 251446Hom.: 0 AF XY: 0.0000221 AC XY: 3AN XY: 135896
GnomAD4 exome AF: 0.00000958 AC: 14AN: 1461830Hom.: 0 Cov.: 31 AF XY: 0.00000688 AC XY: 5AN XY: 727226
GnomAD4 genome AF: 0.00000657 AC: 1AN: 152176Hom.: 0 Cov.: 33 AF XY: 0.0000135 AC XY: 1AN XY: 74326
ClinVar
Submissions by phenotype
Pseudo-Hurler polydystrophy;C2673377:Mucolipidosis type II Pathogenic:2
Likely pathogenic, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Oct 31, 2018 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Oct 17, 2023 | This sequence change replaces cysteine, which is neutral and slightly polar, with tyrosine, which is neutral and polar, at codon 505 of the GNPTAB protein (p.Cys505Tyr). This variant is present in population databases (rs281864980, gnomAD 0.004%). This missense change has been observed in individual(s) with mucolipidosis (PMID: 19617216, 23566849). 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: 39035). 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. Experimental studies have shown that this missense change affects GNPTAB function (PMID: 25505245, 25788519). For these reasons, this variant has been classified as Pathogenic. - |
Pseudo-Hurler polydystrophy Pathogenic:1Other:1
not provided, no classification provided | literature only | GeneReviews | - | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Centre for Mendelian Genomics, University Medical Centre Ljubljana | Jan 18, 2019 | This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PS1,PM2,PP4,PS3,PM3. This variant was detected in homozygous state. - |
Juvenile osteochondrosis of spine;C1442965:Legg-Calve-Perthes disease Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Centre for Mendelian Genomics, University Medical Centre Ljubljana | Jan 01, 2017 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at