4-1003100-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BA1

This summary comes from the ClinGen Evidence Repository: The NM_000203.5:c.1467C>T variant in IDUA is a synonymous (silent) variant (p.Arg489=). The highest population minor allele frequency in gnomAD v4.1.0 is 0.2948 (23904/81086 alleles; 3762 homozygotes; Grpmax Filtering AF 95% confidence = 0.2917) 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: 92632). 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 Disorders 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/CA145874/MONDO:0001586/091

Frequency

Genomes: 𝑓 0.17 ( 2355 hom., cov: 33)

Exomes 𝑓: 0.16 ( 19025 hom. )

Consequence

IDUA
NM_000203.5 synonymous

Scores

Clinical Significance

Benign reviewed by expert panel B:13

Conservation

PhyloP100: -0.905

Publications

15 publications found

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

IDUA links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -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.1467C>T	p.Arg489Arg	synonymous_variant	Exon 10 of 14	ENST00000514224.2	NP_000194.2	P35475-1
IDUA	NM_001363576.1 link	c.1071C>T	p.Arg357Arg	synonymous_variant	Exon 9 of 13		NP_001350505.1
IDUA	XM_047415650.1 link	c.1467C>T	p.Arg489Arg	synonymous_variant	Exon 10 of 12		XP_047271606.1
IDUA	NR_110313.1 link	n.1555C>T		non_coding_transcript_exon_variant	Exon 10 of 14

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
IDUA	ENST00000514224.2 link	c.1467C>T	p.Arg489Arg	synonymous_variant	Exon 10 of 14	2	NM_000203.5	ENSP00000425081.2		P35475-1

Frequencies

GnomAD3 genomes

AF:

0.172

AC:

26134

AN:

151710

Hom.:

2359

Cov.:

show subpopulations

Gnomad AFR

AF:

0.212

Gnomad AMI

AF:

0.170

Gnomad AMR

AF:

0.124

Gnomad ASJ

AF:

0.165

Gnomad EAS

AF:

0.201

Gnomad SAS

AF:

0.299

Gnomad FIN

AF:

0.144

Gnomad MID

AF:

0.236

Gnomad NFE

AF:

0.152

Gnomad OTH

AF:

0.183

GnomAD2 exomes

AF:

0.174

AC:

25755

AN:

148148

AF XY:

0.186

show subpopulations

Gnomad AFR exome

AF:

0.220

Gnomad AMR exome

AF:

0.0699

Gnomad ASJ exome

AF:

0.159

Gnomad EAS exome

AF:

0.216

Gnomad FIN exome

AF:

0.157

Gnomad NFE exome

AF:

0.163

Gnomad OTH exome

AF:

0.175

GnomAD4 exome

AF:

0.161

AC:

218886

AN:

1362958

Hom.:

19025

Cov.:

AF XY:

0.165

AC XY:

111298

AN XY:

676220

show subpopulations

African (AFR)

AF:

0.220

AC:

6250

AN:

28416

American (AMR)

AF:

0.0799

AC:

2721

AN:

34054

Ashkenazi Jewish (ASJ)

AF:

0.160

AC:

3817

AN:

23928

East Asian (EAS)

AF:

0.162

AC:

5099

AN:

31398

South Asian (SAS)

AF:

0.295

AC:

22463

AN:

76256

European-Finnish (FIN)

AF:

0.158

AC:

5584

AN:

35346

Middle Eastern (MID)

AF:

0.203

AC:

1107

AN:

5462

European-Non Finnish (NFE)

AF:

0.152

AC:

162435

AN:

1071866

Other (OTH)

AF:

0.167

AC:

9410

AN:

56232

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.485

Heterozygous variant carriers

9602

19204

28805

38407

48009

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

6002

12004

18006

24008

30010

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.172

AC:

26131

AN:

151818

Hom.:

2355

Cov.:

AF XY:

0.172

AC XY:

12796

AN XY:

74224

show subpopulations

African (AFR)

AF:

0.212

AC:

8776

AN:

41432

American (AMR)

AF:

0.123

AC:

1883

AN:

15278

Ashkenazi Jewish (ASJ)

AF:

0.165

AC:

571

AN:

3460

East Asian (EAS)

AF:

0.200

AC:

1027

AN:

5128

South Asian (SAS)

AF:

0.298

AC:

1441

AN:

4830

European-Finnish (FIN)

AF:

0.144

AC:

1515

AN:

10530

Middle Eastern (MID)

AF:

0.229

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.152

AC:

10313

AN:

67852

Other (OTH)

AF:

0.182

AC:

384

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.489

Heterozygous variant carriers

1063

2126

3190

4253

5316

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

288

576

864

1152

1440

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.151

Hom.:

236

Bravo

AF:

0.169

Asia WGS

AF:

0.248

AC:

861

AN:

3450

ClinVar

Significance: Benign

Submissions summary: Benign:13

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

not specified

Benign:5

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Nov 02, 2017

Eurofins Ntd Llc (ga)

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

- -

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Mucopolysaccharidosis type 1

Benign:4

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. -

May 11, 2017

Natera, Inc.

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

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.1467C>T variant in IDUA is a synonymous (silent) variant (p.Arg489=). The highest population minor allele frequency in gnomAD v4.1.0 is 0.2948 (23904/81086 alleles; 3762 homozygotes; Grpmax Filtering AF 95% confidence = 0.2917) 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: 92632). 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 Disorders 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:3

Jul 05, 2018

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jan 29, 2016

Mayo Clinic Laboratories, Mayo Clinic

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Hurler syndrome

Benign:1

Apr 04, 2024

Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre

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

-0.74

CADD

Benign

6.4

(source)

DANN

Benign

0.88

PhyloP100

-0.91

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Mutation Taster

=100/0

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over