4-1002945-G-A

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM3PM2_SupportingPP4PVS1_Strong

This summary comes from the ClinGen Evidence Repository: The NM_000203.5:c.1402+1G>A variant in IDUA occurs within the canonical splice donor site of intron 9. While the effect of this change has not been proven experimentally, it is predicted to cause skipping of biologically-relevant-exon 9 out of 14 total exons, resulting in an in-frame deletion of amino acids 397-467 which represents >10% of the protein (PVS1_Strong). This variant has been detected in at least two individuals with MPS I. Of those individuals, one was compound heterozygous for the variant and c.502G>T p.(Gly168Ter), which is classified as pathogenic by the ClinGen Lysosomal Diseases VCEP; it is unknown if these variants were confirmed in trans (PMID:33301762). The other individual was homozygous for the variant (PMID:27146977) (PM3). These two patients had documented IDUA deficiency within the affected range in leukocytes and clinical features specific to MPS I including coarse facies, hepatosplenomegaly, corneal opacity, recurrent infections, intellectual disability, hernia, and/or cardiomegaly, cardiomyopathy, and dysostosis multiplex (PP4)(PMIDs: 33301762, 27146977). This variant is absent in gnomAD v4.0. (PM2_Supporting). There is a ClinVar entry for this variant (Variation ID: 555490). In summary, this variant meets the criteria to be classified as likely pathogenic for MPS I based on the IDUA-specific ACMG/AMP criteria applied, as specified by the ClinGen Lysosomal Diseases Variant Curation Expert Panel (Specifications Version 1.0.0): (PVS1_Strong, PM3, PP4, PM2_Supporting).(Classification approved by the ClinGen Lysosomal Diseases Variant Curation Expert Panel on December 5, 2024). LINK:https://erepo.genome.network/evrepo/ui/classification/CA355964379/MONDO:0001586/091

Frequency

Genomes: not found (cov: 33)
Exomes 𝑓: 0.0 ( 0 hom. )
Failed GnomAD Quality Control

Consequence

IDUA
NM_000203.5 splice_donor, intron

Scores

2
2
3
Splicing: ADA: 1.000
2

Clinical Significance

Likely pathogenic criteria provided, multiple submitters, no conflicts P:2

Conservation

PhyloP100: 3.51
Variant links:
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 Likely_pathogenic. Variant got 8 ACMG points.

PVS1
For more information check the summary or visit ClinGen Evidence Repository.
PM2
For more information check the summary or visit ClinGen Evidence Repository.
PM3
For more information check the summary or visit ClinGen Evidence Repository.
PP4
For more information check the summary or visit ClinGen Evidence Repository.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
IDUANM_000203.5 linkc.1402+1G>A splice_donor_variant, intron_variant ENST00000514224.2 NP_000194.2 P35475-1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
IDUAENST00000514224.2 linkc.1402+1G>A splice_donor_variant, intron_variant 2 NM_000203.5 ENSP00000425081.2 P35475-1

Frequencies

GnomAD3 genomes
Cov.:
33
GnomAD4 exome
Data not reliable, filtered out with message: AC0
AF:
0.00
AC:
0
AN:
1209636
Hom.:
0
Cov.:
36
AF XY:
0.00
AC XY:
0
AN XY:
586794
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
33

ClinVar

Significance: Likely pathogenic
Submissions summary: Pathogenic:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Hurler syndrome Pathogenic:1
Likely pathogenic, criteria provided, single submitterclinical testingCounsylDec 06, 2017- -
Mucopolysaccharidosis, MPS-I-S;C0086431:Mucopolysaccharidosis, MPS-I-H/S;C0086795:Hurler syndrome Pathogenic:1
Likely pathogenic, criteria provided, single submitterclinical testingFulgent Genetics, Fulgent GeneticsMar 24, 2024- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
0.63
D
BayesDel_noAF
Benign
-0.18
CADD
Pathogenic
27
DANN
Uncertain
0.98
Eigen
Pathogenic
0.71
Eigen_PC
Uncertain
0.45
FATHMM_MKL
Benign
0.58
D
GERP RS
4.3

Splicing

Name
Calibrated prediction
Score
Prediction
dbscSNV1_ADA
Pathogenic
1.0
dbscSNV1_RF
Pathogenic
0.94
SpliceAI score (max)
1.0
Details are displayed if max score is > 0.2
DS_DL_spliceai
1.0
Position offset: -1

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs398123254; hg19: chr4-996733; API