rs3755954

Positions:

chr4-1000664-C-T

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.352C>T variant in IDUA is a synonymous (silent) variant (p.Leu118=). The highest population minor allele frequency in gnomAD v4.1.0 is 0.2517 (296774/1178988 alleles; 37458 homozygotes) in the European non-Finnish 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: 92642). 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/CA145883/MONDO:0001586/091

Frequency

Genomes: 𝑓 0.22 ( 3827 hom., cov: 34)

Exomes 𝑓: 0.23 ( 40947 hom. )

Consequence

IDUA
NM_001363576.1 5_prime_UTR_premature_start_codon_gain

Scores

Clinical Significance

Benign reviewed by expert panel B:16

Conservation

PhyloP100: -0.107

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:

IDUA (HGNC:):

IDUA links:

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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/exons	MANE	Protein	UniProt
IDUA	NM_000203.5 linkuse as main transcript	c.352C>T	p.Leu118Leu	synonymous_variant	3/14	ENST00000514224.2	NP_000194.2	P35475-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
IDUA	ENST00000514224.2 linkuse as main transcript	c.352C>T	p.Leu118Leu	synonymous_variant	3/14	2	NM_000203.5	ENSP00000425081.2		P35475-1

Frequencies

GnomAD3 genomes

AF:

0.217

AC:

33067

AN:

152108

Hom.:

3823

Cov.:

show subpopulations

Gnomad AFR

AF:

0.192

Gnomad AMI

AF:

0.342

Gnomad AMR

AF:

0.211

Gnomad ASJ

AF:

0.135

Gnomad EAS

AF:

0.152

Gnomad SAS

AF:

0.0661

Gnomad FIN

AF:

0.242

Gnomad MID

AF:

0.101

Gnomad NFE

AF:

0.250

Gnomad OTH

AF:

0.198

GnomAD3 exomes

AF:

0.202

AC:

50493

AN:

250192

Hom.:

5611

AF XY:

0.195

AC XY:

26513

AN XY:

135702

show subpopulations

Gnomad AFR exome

AF:

0.192

Gnomad AMR exome

AF:

0.228

Gnomad ASJ exome

AF:

0.133

Gnomad EAS exome

AF:

0.147

Gnomad SAS exome

AF:

0.0691

Gnomad FIN exome

AF:

0.242

Gnomad NFE exome

AF:

0.238

Gnomad OTH exome

AF:

0.205

GnomAD4 exome

AF:

0.231

AC:

336889

AN:

1459400

Hom.:

40947

Cov.:

AF XY:

0.225

AC XY:

163665

AN XY:

726026

show subpopulations

Gnomad4 AFR exome

AF:

0.189

Gnomad4 AMR exome

AF:

0.226

Gnomad4 ASJ exome

AF:

0.134

Gnomad4 EAS exome

AF:

0.128

Gnomad4 SAS exome

AF:

0.0723

Gnomad4 FIN exome

AF:

0.242

Gnomad4 NFE exome

AF:

0.252

Gnomad4 OTH exome

AF:

0.211

GnomAD4 genome

AF:

0.217

AC:

33093

AN:

152226

Hom.:

3827

Cov.:

AF XY:

0.213

AC XY:

15834

AN XY:

74438

show subpopulations

Gnomad4 AFR

AF:

0.192

Gnomad4 AMR

AF:

0.211

Gnomad4 ASJ

AF:

0.135

Gnomad4 EAS

AF:

0.152

Gnomad4 SAS

AF:

0.0668

Gnomad4 FIN

AF:

0.242

Gnomad4 NFE

AF:

0.250

Gnomad4 OTH

AF:

0.196

Alfa

AF:

0.233

Hom.:

4611

Bravo

AF:

0.218

Asia WGS

AF:

0.102

AC:

357

AN:

3478

EpiCase

AF:

0.229

EpiControl

AF:

0.226

ClinVar

Significance: Benign

Submissions summary: Benign:16

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

not specified

Benign:6

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	May 25, 2018	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -

Mucopolysaccharidosis type 1

Benign:4

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	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. -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Benign, reviewed by expert panel	curation	ClinGen Lysosomal Storage Disorder Variant Curation Expert Panel	Dec 06, 2024	The NM_000203.5:c.352C>T variant in IDUA is a synonymous (silent) variant (p.Leu118=). The highest population minor allele frequency in gnomAD v4.1.0 is 0.2517 (296774/1178988 alleles; 37458 homozygotes) in the European non-Finnish 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: 92642). 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) -
Benign, no assertion criteria provided	clinical testing	Natera, Inc.	May 11, 2017	- -

not provided

Benign:3

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, no assertion criteria provided	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Oct 20, 2015	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Aug 31, 2018	This variant is associated with the following publications: (PMID: 9700243, 12509712, 19396826) -

Mucopolysaccharidosis, MPS-I-H/S

Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 10, 2021

- -

Mucopolysaccharidosis, MPS-I-S

Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 10, 2021

- -

Hurler syndrome

Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 10, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.78

CADD

Benign

6.2

DANN

Benign

0.60

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

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