rs398123254

Variant names:

• chr4-1002945-G-A
• rs398123254
• NM_000203.5:c.1402+1G>A

Your query was ambiguous. Multiple possible variants found:

• chr4-1002945-G-A
• chr4-1002945-G-C
• chr4-1002945-G-T

Variant summary

Our verdict is Likely pathogenic. The variant received 8 ACMG points: 8P and 0B. PM3 PM2_Supporting PP4 PVS1_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: Splicing: ADA: 1.000
• Clinical Significance: Likely pathogenic reviewed by expert panel P:3
• Conservation: PhyloP100: 3.51
• Publications: 1 publications found

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]

IDUA Gene-Disease associations (from GenCC):

• mucopolysaccharidosis type 1

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen, Myriad Women's Health
• Scheie syndrome

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Genomics England PanelApp, Orphanet, G2P, Labcorp Genetics (formerly Invitae)
• Hurler syndrome

  Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Genomics England PanelApp, Orphanet
• Hurler-Scheie syndrome

  Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Genomics England PanelApp, Orphanet

ACMG classification

Specifications for IDUA are available in the ClinGen Criteria Specification Registry and recommended for reference when assigning criteria.

Our verdict: Likely_pathogenic. The variant received 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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000203.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IDUA	NM_000203.5	MANE Select	c.1402+1G>A		splice_donor intron	N/A	NP_000194.2	P35475-1
	IDUA	NM_001363576.1		c.1006+1G>A		splice_donor intron	N/A	NP_001350505.1
	IDUA	NR_110313.1		n.1490+1G>A		splice_donor intron	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IDUA	ENST00000514224.2	TSL:2 MANE Select	c.1402+1G>A		splice_donor intron	N/A	ENSP00000425081.2	P35475-1
	IDUA	ENST00000247933.9	TSL:1	c.1402+1G>A		splice_donor intron	N/A	ENSP00000247933.4	P35475-1
	IDUA	ENST00000962389.1		c.1477+1G>A		splice_donor intron	N/A	ENSP00000632448.1

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

African (AFR) AF: 0.00 AC: 0 AN: 23674

American (AMR) AF: 0.00 AC: 0 AN: 10208

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 16938

East Asian (EAS) AF: 0.00 AC: 0 AN: 27262

South Asian (SAS) AF: 0.00 AC: 0 AN: 51490

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 29164

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4198

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 996884

Other (OTH) AF: 0.00 AC: 0 AN: 49818

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions

Significance: Likely pathogenic

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
1	-	-	Hurler syndrome (1)
1	-	-	Mucopolysaccharidosis type 1 (1)
1	-	-	Mucopolysaccharidosis, MPS-I-S;C0086431:Mucopolysaccharidosis, MPS-I-H/S;C0086795:Hurler syndrome (1)

Computational scores

Source: dbNSFP v4.9

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
PhyloP100		3.5
Mutation Taster		=0/100	disease causing (ClinVar)

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs398123254;

hg19: chr4-996733;