chr4-1003100-C-T

Variant names:

• chr4-1003100-C-T
• rs115929690
• NM_000203.5:c.1467C>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.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
• Clinical Significance: Benign reviewed by expert panel B:13
• Conservation: PhyloP100: -0.905

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]

ACMG classification

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	c.1467C>T	p.Arg489Arg	synonymous_variant	Exon 10 of 14	ENST00000514224.2	NP_000194.2

Ensembl

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

Frequencies

GnomAD3 genomes AF: 0.172 AC: 26134 AN: 151710 Hom.: 2359 Cov.: 33

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

GnomAD3 exomes AF: 0.174 AC: 25755 AN: 148148 Hom.: 2596 AF XY: 0.186 AC XY: 15807 AN XY: 85208

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 SAS exome AF: 0.295

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.: 37 AF XY: 0.165 AC XY: 111298 AN XY: 676220

Gnomad4 AFR exome AF: 0.220

Gnomad4 AMR exome AF: 0.0799

Gnomad4 ASJ exome AF: 0.160

Gnomad4 EAS exome AF: 0.162

Gnomad4 SAS exome AF: 0.295

Gnomad4 FIN exome AF: 0.158

Gnomad4 NFE exome AF: 0.152

Gnomad4 OTH exome AF: 0.167

GnomAD4 genome AF: 0.172 AC: 26131 AN: 151818 Hom.: 2355 Cov.: 33 AF XY: 0.172 AC XY: 12796 AN XY: 74224

Gnomad4 AFR AF: 0.212

Gnomad4 AMR AF: 0.123

Gnomad4 ASJ AF: 0.165

Gnomad4 EAS AF: 0.200

Gnomad4 SAS AF: 0.298

Gnomad4 FIN AF: 0.144

Gnomad4 NFE AF: 0.152

Gnomad4 OTH AF: 0.182

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

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

- -

-

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

- -

-

PreventionGenetics, part of Exact Sciences

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

- -

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) -

May 11, 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. -

not provided Benign:3

Jan 29, 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

- -

-

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
DANN	Benign	0.88
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

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

Other links and lift over

dbSNP: rs115929690; hg19: chr4-996888; COSMIC: COSV56103390; COSMIC: COSV56103390;