rs398123256
Positions:
Variant summary
Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM2PP3PP5_Very_Strong
The NM_000203.5(IDUA):c.1650+5G>A variant causes a splice donor 5th base, intron change. The variant allele was found at a frequency of 0.00000701 in 1,425,586 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 1/1 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★★).
Frequency
Genomes: not found (cov: 33)
Exomes 𝑓: 0.0000070 ( 0 hom. )
Consequence
IDUA
NM_000203.5 splice_donor_5th_base, intron
NM_000203.5 splice_donor_5th_base, intron
Scores
2
Clinical Significance
Conservation
PhyloP100: 4.49
Genes affected
IDUA (HGNC:5391): (alpha-L-iduronidase) This gene encodes an enzyme that hydrolyzes the terminal alpha-L-iduronic acid residues of two glycosaminoglycans, dermatan sulfate and heparan sulfate. This hydrolysis is required for the lysosomal degradation of these glycosaminoglycans. Mutations in this gene that result in enzymatic deficiency lead to the autosomal recessive disease mucopolysaccharidosis type I (MPS I). [provided by RefSeq, Jul 2008]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 11 ACMG points.
PM2
Very rare variant in population databases, with high coverage;
PP3
Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
PP5
Variant 4-1003475-G-A is Pathogenic according to our data. Variant chr4-1003475-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 92634.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
IDUA | NM_000203.5 | c.1650+5G>A | splice_donor_5th_base_variant, intron_variant | ENST00000514224.2 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
IDUA | ENST00000514224.2 | c.1650+5G>A | splice_donor_5th_base_variant, intron_variant | 2 | NM_000203.5 | P1 |
Frequencies
GnomAD3 genomes Cov.: 33
GnomAD3 genomes
Cov.:
33
GnomAD4 exome AF: 0.00000701 AC: 10AN: 1425586Hom.: 0 Cov.: 34 AF XY: 0.00000848 AC XY: 6AN XY: 707768
GnomAD4 exome
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1425586
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34
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6
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707768
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GnomAD4 genome Cov.: 33
GnomAD4 genome
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33
Bravo
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ClinVar
Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:4
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not provided Pathogenic:2
Likely pathogenic, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Nov 07, 2019 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Dec 06, 2012 | - - |
Mucopolysaccharidosis type 1 Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Apr 23, 2023 | For these reasons, this variant has been classified as Pathogenic. Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. ClinVar contains an entry for this variant (Variation ID: 92634). This variant is also known as IVS11+5G>A. This variant has been observed in individual(s) with mucopolysaccharidosis type I (PMID: 12203999, 19396826, 21394825). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is not present in population databases (gnomAD no frequency). This sequence change falls in intron 11 of the IDUA gene. It does not directly change the encoded amino acid sequence of the IDUA protein. It affects a nucleotide within the consensus splice site. - |
Hurler syndrome Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Counsyl | Aug 03, 2017 | - - |
Computational scores
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Name
Calibrated prediction
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BayesDel_noAF
Benign
CADD
Benign
DANN
Benign
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
DS_DL_spliceai
Position offset: -5
Find out detailed SpliceAI scores and Pangolin per-transcript scores at