4-1001671-C-T

Variant names:

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BA1

This summary comes from the ClinGen Evidence Repository: The NM_000203.5:c.590-8C>T variant is a nucleotide substitution in the acceptor splice site region of intron 5 of IDUA. The highest population minor allele frequency in gnomAD v4.1.0 is 0.2984 (27112/90864 alleles; 4285 homozygotes; Grpmax Filtering AF 95% confidence = 0.2954) in the South Asian population, which is higher than the ClinGen Lysosomal Diseases VCEP’s threshold for BA1 (>0.005), and therefore meets this criterion (BA1). There is a ClinVar entry for this variant (Variation ID: 92646). In summary, this variant meets the criteria to be classified as benign for mucopolysaccharidosis type 1. IDUA-specific ACMG/AMP criteria applied, as specified by the ClinGen Lysosomal Diseases Variant Curation Expert Panel (Specifications Version 1.0.0): BA1.(Classification approved by the ClinGen Lysosomal Diseases Variant Curation Expert Panel on December 6, 2024) LINK:https://erepo.genome.network/evrepo/ui/classification/CA145887/MONDO:0001586/091

Frequency

Genomes: 𝑓 0.17 ( 2376 hom., cov: 33)

Exomes 𝑓: 0.16 ( 20716 hom. )

Consequence

IDUA
NM_000203.5 splice_region, intron

Scores

Splicing: ADA: 0.00006631

Clinical Significance

Benign reviewed by expert panel B:16

Conservation

PhyloP100: -0.00700

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]

IDUA links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -8 ACMG points.

BA1

For more information check the summary or visit ClinGen Evidence Repository.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
IDUA	NM_000203.5 link	c.590-8C>T		splice_region_variant, intron_variant	Intron 5 of 13	ENST00000514224.2	NP_000194.2	P35475-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
IDUA	ENST00000514224.2 link	c.590-8C>T		splice_region_variant, intron_variant	Intron 5 of 13	2	NM_000203.5	ENSP00000425081.2		P35475-1

Frequencies

GnomAD3 genomes

AF:

0.173

AC:

26284

AN:

152010

Hom.:

2380

Cov.:

show subpopulations

Gnomad AFR

AF:

0.213

Gnomad AMI

AF:

0.169

Gnomad AMR

AF:

0.124

Gnomad ASJ

AF:

0.166

Gnomad EAS

AF:

0.200

Gnomad SAS

AF:

0.301

Gnomad FIN

AF:

0.144

Gnomad MID

AF:

0.234

Gnomad NFE

AF:

0.153

Gnomad OTH

AF:

0.182

GnomAD3 exomes

AF:

0.176

AC:

40992

AN:

233562

Hom.:

4034

AF XY:

0.184

AC XY:

23550

AN XY:

127814

show subpopulations

Gnomad AFR exome

AF:

0.217

Gnomad AMR exome

AF:

0.0790

Gnomad ASJ exome

AF:

0.160

Gnomad EAS exome

AF:

0.215

Gnomad SAS exome

AF:

0.300

Gnomad FIN exome

AF:

0.155

Gnomad NFE exome

AF:

0.162

Gnomad OTH exome

AF:

0.175

GnomAD4 exome

AF:

0.163

AC:

235600

AN:

1449094

Hom.:

20716

Cov.:

AF XY:

0.167

AC XY:

120254

AN XY:

721078

show subpopulations

Gnomad4 AFR exome

AF:

0.220

Gnomad4 AMR exome

AF:

0.0844

Gnomad4 ASJ exome

AF:

0.160

Gnomad4 EAS exome

AF:

0.171

Gnomad4 SAS exome

AF:

0.298

Gnomad4 FIN exome

AF:

0.155

Gnomad4 NFE exome

AF:

0.153

Gnomad4 OTH exome

AF:

0.169

GnomAD4 genome

AF:

0.173

AC:

26281

AN:

152128

Hom.:

2376

Cov.:

AF XY:

0.173

AC XY:

12863

AN XY:

74382

show subpopulations

Gnomad4 AFR

AF:

0.212

Gnomad4 AMR

AF:

0.123

Gnomad4 ASJ

AF:

0.166

Gnomad4 EAS

AF:

0.200

Gnomad4 SAS

AF:

0.300

Gnomad4 FIN

AF:

0.144

Gnomad4 NFE

AF:

0.153

Gnomad4 OTH

AF:

0.181

Alfa

AF:

0.125

Hom.:

540

Bravo

AF:

0.170

ClinVar

Significance: Benign

Submissions summary: Benign:16

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

not specified

Benign:5

Nov 02, 2017

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Clinical Genetics, Academic Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Mucopolysaccharidosis type 1

Benign:4

Aug 08, 2017

Natera, Inc.

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Dec 06, 2024

ClinGen Lysosomal Storage Disorder Variant Curation Expert Panel

Significance: Benign

Review Status: reviewed by expert panel

Collection Method: curation

The NM_000203.5:c.590-8C>T variant is a nucleotide substitution in the acceptor splice site region of intron 5 of IDUA. The highest population minor allele frequency in gnomAD v4.1.0 is 0.2984 (27112/90864 alleles; 4285 homozygotes; Grpmax Filtering AF 95% confidence = 0.2954) in the South Asian population, which is higher than the ClinGen Lysosomal Diseases VCEP’s threshold for BA1 (>0.005), and therefore meets this criterion (BA1). There is a ClinVar entry for this variant (Variation ID: 92646). In summary, this variant meets the criteria to be classified as benign for mucopolysaccharidosis type 1. IDUA-specific ACMG/AMP criteria applied, as specified by the ClinGen Lysosomal Diseases Variant Curation Expert Panel (Specifications Version 1.0.0): BA1. (Classification approved by the ClinGen Lysosomal Diseases Variant Curation Expert Panel on December 6, 2024) -

not provided

Benign:4

Jan 15, 2016

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Feb 02, 2016

Mayo Clinic Laboratories, Mayo Clinic

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Jul 05, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mucopolysaccharidosis, MPS-I-H/S

Benign:1

Jul 10, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mucopolysaccharidosis, MPS-I-S

Benign:1

Jul 10, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Hurler syndrome

Benign:1

Jul 10, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.82

CADD

Benign

1.0

DANN

Benign

0.63

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.000066

dbscSNV1_RF

Benign

0.0020

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over