rs762411583
Variant summary
Our verdict is Likely pathogenic. Variant got 9 ACMG points: 10P and 1B. PM2PP5_Very_StrongBP4
The NM_000203.5(IDUA):c.590-7G>A variant causes a splice region, splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000312 in 1,601,952 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Pathogenic (★★).
Frequency
Consequence
NM_000203.5 splice_region, splice_polypyrimidine_tract, intron
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_pathogenic. Variant got 9 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
IDUA | NM_000203.5 | c.590-7G>A | splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant | ENST00000514224.2 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
IDUA | ENST00000514224.2 | c.590-7G>A | splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant | 2 | NM_000203.5 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.00000657 AC: 1AN: 152152Hom.: 0 Cov.: 34
GnomAD3 exomes AF: 0.00000427 AC: 1AN: 234380Hom.: 0 AF XY: 0.00000779 AC XY: 1AN XY: 128322
GnomAD4 exome AF: 0.0000338 AC: 49AN: 1449800Hom.: 0 Cov.: 34 AF XY: 0.0000333 AC XY: 24AN XY: 721532
GnomAD4 genome ? AF: 0.00000657 AC: 1AN: 152152Hom.: 0 Cov.: 34 AF XY: 0.00 AC XY: 0AN XY: 74324
ClinVar
Submissions by phenotype
Mucopolysaccharidosis type 1 Pathogenic:3Other:1
not provided, no classification provided | literature only | GeneReviews | - | Variant causes attenuated MPS I; creates alternate splice site, but (as old splice site is not obliterated) some normal enzyme is produced. - |
Likely pathogenic, no assertion criteria provided | clinical testing | Natera, Inc. | Sep 16, 2020 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Dec 09, 2023 | This sequence change falls in intron 5 of the IDUA gene. It does not directly change the encoded amino acid sequence of the IDUA protein. RNA analysis indicates that this variant induces altered splicing and may result in an absent or disrupted protein product. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This variant has been observed in individuals with Scheie syndrome (PMID: 8213840, 28752568). This variant is also known as 678-7G>A. ClinVar contains an entry for this variant (Variation ID: 222996). Studies have shown that this variant results in activation of a cryptic splice acceptor and introduces a premature termination codon (PMID: 8318992). The resulting mRNA is expected to undergo nonsense-mediated decay. For these reasons, this variant has been classified as Pathogenic. - |
Pathogenic, criteria provided, single submitter | curation | Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard | Jan 14, 2020 | The c.590-7G>A variant in IDUA has been reported in at least 10 individuals with mucopolysaccharidosis (MPS) (PMID: 28752568, 8213840, 9748610) and has been identified in 0.001% (1/106874) of European (non-Finnish) chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs762411583). Although this variant has been seen in the general population, its frequency is low enough to be consistent with a recessive carrier frequency. This variant has also been reported in ClinVar (VariationID: 222996) as pathogenic by Counsyl, OMIM, and GeneReviews. Functional studies demonstrating that the variant activates a cryptic splice site provide some evidence that the c.590-7G>A variant may slightly impact protein function (PMID: 8213840). However, these types of assays may not accurately represent biological function. Computational prediction tools and conservation analyses do not provide strong support for or against an impact to the protein. This variant is located in the 3' splice region. Computational tools suggest a possible impact to splicing. However, this information is not predictive enough to determine pathogenicity. The phenotype of individuals compound heterozygous for this variant is high' ly specific for MPS based on their Alpha-L-iduronidase protein levels being <1% consistent with disease (PMID: 9748610, 8213840). In summary, this variant meets criteria to be classified as pathogenic for MPS in an autosomal recessive manner based on the presence of the variant in combination with reported pathogenic variants, the phenotype of patients with the variant being highly specific for MPS, and evidence of aberrant splicing. ACMG/AMP Criteria applied: PM3_very-strong, PM2, PP4, PS3_supporting (Richards 2015). - |
Mucopolysaccharidosis, MPS-I-S Pathogenic:1
Pathogenic, no assertion criteria provided | literature only | OMIM | Nov 01, 1993 | - - |
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Jun 19, 2023 | - - |
Hurler syndrome Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Counsyl | Aug 30, 2017 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at