Genetic Variant IDUA:c.1190-10dupC (chr4-1002713-G-GC) – ACMG Classification: Benign (-8 pts)

Variant summary

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

This summary comes from the ClinGen Evidence Repository: NM_000203.5:c.1190-10dupC variant is in the acceptor splice site region of intron 8 of IDUA. The highest population minor allele frequency in gnomAD v4.1.0 is 0.2350 (16758/71322 alleles; 1409 homozygotes; Grpmax Filtering AF 95% confidence = 0.2320) 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: 92626). 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/CA145869/MONDO:0001586/091

Frequency

Genomes: 𝑓 0.16 ( 2046 hom., cov: 29)

Exomes 𝑓: 0.093 ( 3064 hom. )

Failed GnomAD Quality Control

Consequence

IDUA
NM_000203.5 intron

Scores

Not classified

Clinical Significance

Benign reviewed by expert panel B:10

Conservation

PhyloP100: -0.792

Publications

3 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: Myriad Women’s Health, ClinGen
Scheie syndrome
Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, Genomics England PanelApp, Labcorp Genetics (formerly Invitae), G2P
Hurler syndrome
Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Orphanet, Genomics England PanelApp
Hurler-Scheie syndrome
Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Genomics England PanelApp, Orphanet

IDUA links:

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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.

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

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
IDUA	NM_000203.5	MANE Select	c.1190-10dupC	intron	N/A	NP_000194.2	P35475-1
IDUA	NM_001363576.1		c.794-10dupC	intron	N/A	NP_001350505.1
IDUA	NR_110313.1		n.1278-10dupC	intron	N/A

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
IDUA	ENST00000514224.2	TSL:2 MANE Select	c.1190-19_1190-18insC	intron	N/A	ENSP00000425081.2	P35475-1
IDUA	ENST00000247933.9	TSL:1	c.1190-19_1190-18insC	intron	N/A	ENSP00000247933.4	P35475-1
IDUA	ENST00000962389.1		c.1265-19_1265-18insC	intron	N/A	ENSP00000632448.1

Frequencies

GnomAD3 genomes

AF:

0.164

AC:

24511

AN:

149414

Hom.:

2051

Cov.:

show subpopulations

Gnomad AFR

AF:

0.192

Gnomad AMI

AF:

0.158

Gnomad AMR

AF:

0.122

Gnomad ASJ

AF:

0.167

Gnomad EAS

AF:

0.192

Gnomad SAS

AF:

0.297

Gnomad FIN

AF:

0.136

Gnomad MID

AF:

0.222

Gnomad NFE

AF:

0.149

Gnomad OTH

AF:

0.175

GnomAD2 exomes

AF:

0.160

AC:

11726

AN:

73188

AF XY:

0.174

show subpopulations

Gnomad AFR exome

AF:

0.172

Gnomad AMR exome

AF:

0.0747

Gnomad ASJ exome

AF:

0.154

Gnomad EAS exome

AF:

0.195

Gnomad FIN exome

AF:

0.147

Gnomad NFE exome

AF:

0.148

Gnomad OTH exome

AF:

0.169

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.0927

AC:

110358

AN:

1190586

Hom.:

3064

Cov.:

AF XY:

0.0998

AC XY:

58876

AN XY:

590056

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.118

AC:

2785

AN:

23522

American (AMR)

AF:

0.0725

AC:

2090

AN:

28818

Ashkenazi Jewish (ASJ)

AF:

0.127

AC:

2806

AN:

22104

East Asian (EAS)

AF:

0.126

AC:

3564

AN:

28268

South Asian (SAS)

AF:

0.231

AC:

15368

AN:

66622

European-Finnish (FIN)

AF:

0.141

AC:

4564

AN:

32354

Middle Eastern (MID)

AF:

0.149

AC:

529

AN:

3552

European-Non Finnish (NFE)

AF:

0.0784

AC:

73355

AN:

935346

Other (OTH)

AF:

0.106

AC:

5297

AN:

50000

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.361

Heterozygous variant carriers

5191

10383

15574

20766

25957

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

2056

4112

6168

8224

10280

<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:

0.164

AC:

24506

AN:

149514

Hom.:

2046

Cov.:

AF XY:

0.164

AC XY:

11960

AN XY:

72964

show subpopulations

African (AFR)

AF:

0.192

AC:

7786

AN:

40624

American (AMR)

AF:

0.121

AC:

1839

AN:

15136

Ashkenazi Jewish (ASJ)

AF:

0.167

AC:

573

AN:

3430

East Asian (EAS)

AF:

0.192

AC:

962

AN:

5018

South Asian (SAS)

AF:

0.296

AC:

1390

AN:

4700

European-Finnish (FIN)

AF:

0.136

AC:

1389

AN:

10220

Middle Eastern (MID)

AF:

0.218

AC:

AN:

280

European-Non Finnish (NFE)

AF:

0.149

AC:

10004

AN:

67142

Other (OTH)

AF:

0.174

AC:

360

AN:

2066

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.461

Heterozygous variant carriers

890

1779

2669

3558

4448

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

274

548

822

1096

1370

<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:

0.0727

Hom.:

107

ClinVar

ClinVar submissions

Significance:Benign

Revision:reviewed by expert panel

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (4)

Mucopolysaccharidosis type 1 (3)

not provided (3)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

PhyloP100

-0.79

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over