rs3755955

Variant names:

Your query was ambiguous. Multiple possible variants found:

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.314G>A variant in IDUA is a missense variant predicted to cause substitution of arginine by glutamine at amino acid 105 (p.Arg105Gln). The highest population minor allele frequency in gnomAD v4.1.0 is 0.2431 (22127/91024 alleles; 2838 homozygotes; Grpmax Filtering AF 95% confidence = 0.2404) 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: 92641). 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/CA145881/MONDO:0001586/091

Frequency

Genomes: 𝑓 0.14 ( 1595 hom., cov: 34)

Exomes 𝑓: 0.15 ( 18412 hom. )

Consequence

IDUA
NM_000203.5 missense

Scores

Clinical Significance

Benign reviewed by expert panel B:17

Conservation

PhyloP100: 0.235

Publications

92 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.314G>A	p.Arg105Gln	missense_variant	Exon 3 of 14	ENST00000514224.2	NP_000194.2	P35475-1
IDUA	XM_047415650.1 link	c.314G>A	p.Arg105Gln	missense_variant	Exon 3 of 12		XP_047271606.1
IDUA	NR_110313.1 link	n.402G>A		non_coding_transcript_exon_variant	Exon 3 of 14
IDUA	NM_001363576.1 link	c.-83G>A		5_prime_UTR_variant	Exon 2 of 13		NP_001350505.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
IDUA	ENST00000514224.2 link	c.314G>A	p.Arg105Gln	missense_variant	Exon 3 of 14	2	NM_000203.5	ENSP00000425081.2		P35475-1

Frequencies

GnomAD3 genomes

AF:

0.142

AC:

21587

AN:

152130

Hom.:

1599

Cov.:

show subpopulations

Gnomad AFR

AF:

0.116

Gnomad AMI

AF:

0.171

Gnomad AMR

AF:

0.107

Gnomad ASJ

AF:

0.164

Gnomad EAS

AF:

0.193

Gnomad SAS

AF:

0.242

Gnomad FIN

AF:

0.144

Gnomad MID

AF:

0.225

Gnomad NFE

AF:

0.152

Gnomad OTH

AF:

0.150

GnomAD2 exomes

AF:

0.157

AC:

39334

AN:

250258

AF XY:

0.165

show subpopulations

Gnomad AFR exome

AF:

0.117

Gnomad AMR exome

AF:

0.0721

Gnomad ASJ exome

AF:

0.157

Gnomad EAS exome

AF:

0.211

Gnomad FIN exome

AF:

0.147

Gnomad NFE exome

AF:

0.159

Gnomad OTH exome

AF:

0.162

GnomAD4 exome

AF:

0.154

AC:

225302

AN:

1458656

Hom.:

18412

Cov.:

AF XY:

0.157

AC XY:

114263

AN XY:

725732

show subpopulations

African (AFR)

AF:

0.116

AC:

3881

AN:

33448

American (AMR)

AF:

0.0760

AC:

3397

AN:

44716

Ashkenazi Jewish (ASJ)

AF:

0.157

AC:

4114

AN:

26124

East Asian (EAS)

AF:

0.158

AC:

6286

AN:

39684

South Asian (SAS)

AF:

0.243

AC:

20955

AN:

86200

European-Finnish (FIN)

AF:

0.152

AC:

7947

AN:

52172

Middle Eastern (MID)

AF:

0.189

AC:

1085

AN:

5726

European-Non Finnish (NFE)

AF:

0.152

AC:

168293

AN:

1110274

Other (OTH)

AF:

0.155

AC:

9344

AN:

60312

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.461

Heterozygous variant carriers

9509

19018

28527

38036

47545

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

6042

12084

18126

24168

30210

<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:

0.142

AC:

21578

AN:

152248

Hom.:

1595

Cov.:

AF XY:

0.142

AC XY:

10588

AN XY:

74438

show subpopulations

African (AFR)

AF:

0.116

AC:

4813

AN:

41556

American (AMR)

AF:

0.107

AC:

1638

AN:

15310

Ashkenazi Jewish (ASJ)

AF:

0.164

AC:

569

AN:

3472

East Asian (EAS)

AF:

0.192

AC:

993

AN:

5166

South Asian (SAS)

AF:

0.243

AC:

1172

AN:

4824

European-Finnish (FIN)

AF:

0.144

AC:

1528

AN:

10608

Middle Eastern (MID)

AF:

0.221

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.152

AC:

10334

AN:

67996

Other (OTH)

AF:

0.147

AC:

310

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

977

1954

2930

3907

4884

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

250

500

750

1000

1250

<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:

0.149

Hom.:

7164

Bravo

AF:

0.136

TwinsUK

AF:

0.165

AC:

612

ALSPAC

AF:

0.159

AC:

611

ESP6500AA

AF:

0.107

AC:

473

ESP6500EA

AF:

0.160

AC:

1376

ExAC

AF:

0.163

AC:

19766

Asia WGS

AF:

0.194

AC:

679

AN:

3478

EpiCase

AF:

0.157

EpiControl

AF:

0.163

ClinVar

Significance: Benign

Submissions summary: Benign:17

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

not specified

Benign:5

Clinical Genetics, Academic 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

- -

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Dec 11, 2015

Eurofins Ntd Llc (ga)

Significance:Benign

Review Status:criteria provided, single submitter

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

- -

not provided

Benign:5

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 03, 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

This variant is associated with the following publications: (PMID: 31473686, 26256109, 21462124, 19396826, 9536518, 21639919, 24053568, 24875751) -

Nov 29, 2023

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Mucopolysaccharidosis type 1

Benign:4

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jan 13, 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. -

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.314G>A variant in IDUA is a missense variant predicted to cause substitution of arginine by glutamine at amino acid 105 (p.Arg105Gln). The highest population minor allele frequency in gnomAD v4.1.0 is 0.2431 (22127/91024 alleles; 2838 homozygotes; Grpmax Filtering AF 95% confidence = 0.2404) 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: 92641). 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) -

May 11, 2017

Natera, Inc.

Significance:Benign

Review Status:no assertion criteria provided

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

AlphaMissense

Benign

0.067

BayesDel_addAF

Benign

-0.46

BayesDel_noAF

Benign

-0.29

CADD

Benign

0.74

(source)

DANN

Benign

0.77

DEOGEN2

Uncertain

0.46

T;.;T;T

Eigen

Benign

-1.6

Eigen_PC

Benign

-1.5

FATHMM_MKL

Benign

0.035

LIST_S2

Benign

0.41

T;T;.;.

MetaRNN

Benign

0.0045

T;T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

-0.91

N;.;.;.

PhyloP100

0.23

PrimateAI

Benign

0.20

PROVEAN

Benign

0.050

N;N;N;N

REVEL

Uncertain

0.32

Sift

Benign

1.0

T;T;T;T

Sift4G

Benign

0.72

T;T;T;T

Polyphen

0.0030

B;.;.;.

Vest4

0.019

MPC

0.22

ClinPred

0.000033

GERP RS

1.5

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.056

gMVP

0.55

Mutation Taster

=96/4

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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