rs6815946

Variant names:

• chr4-1001517-T-C
• rs6815946
• NM_000203.5:c.543T>C

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.543T>C variant in IDUA is a synonymous (silent) variant (p.Asn181=). The Grpmax Filtering AF (95% confidence) in gnomAD v4.1.0 is 0.2950 in the South Asian population. This 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: 92645). 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 January 2, 2025) LINK:https://erepo.genome.network/evrepo/ui/classification/CA145885/MONDO:0001586/091

• Frequency:
  • Genomes: 𝑓 0.17 (2398 hom., cov: 33)
  • Exomes 𝑓: 0.16 (20855 hom.)
• Consequence: IDUA NM_000203.5 synonymous
• Clinical Significance: Benign reviewed by expert panel B:15
• Conservation: PhyloP100: -1.19

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.543T>C	p.Asn181Asn	synonymous_variant	Exon 5 of 14	ENST00000514224.2	NP_000194.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
IDUA	ENST00000514224.2	c.543T>C	p.Asn181Asn	synonymous_variant	Exon 5 of 14	2	NM_000203.5	ENSP00000425081.2

Frequencies

GnomAD3 genomes AF: 0.173 AC: 26368 AN: 152000 Hom.: 2402 Cov.: 33

Gnomad AFR AF: 0.215

Gnomad AMI AF: 0.171

Gnomad AMR AF: 0.124

Gnomad ASJ AF: 0.166

Gnomad EAS AF: 0.199

Gnomad SAS AF: 0.300

Gnomad FIN AF: 0.145

Gnomad MID AF: 0.234

Gnomad NFE AF: 0.153

Gnomad OTH AF: 0.182

GnomAD3 exomes AF: 0.173 AC: 43316 AN: 250892 Hom.: 4280 AF XY: 0.181 AC XY: 24586 AN XY: 135794

Gnomad AFR exome AF: 0.217

Gnomad AMR exome AF: 0.0788

Gnomad ASJ exome AF: 0.160

Gnomad EAS exome AF: 0.213

Gnomad SAS exome AF: 0.299

Gnomad FIN exome AF: 0.147

Gnomad NFE exome AF: 0.160

Gnomad OTH exome AF: 0.174

GnomAD4 exome AF: 0.162 AC: 237274 AN: 1460884 Hom.: 20855 Cov.: 34 AF XY: 0.167 AC XY: 121007 AN XY: 726742

Gnomad4 AFR exome AF: 0.223

Gnomad4 AMR exome AF: 0.0844

Gnomad4 ASJ exome AF: 0.161

Gnomad4 EAS exome AF: 0.171

Gnomad4 SAS exome AF: 0.298

Gnomad4 FIN exome AF: 0.152

Gnomad4 NFE exome AF: 0.153

Gnomad4 OTH exome AF: 0.168

GnomAD4 genome AF: 0.173 AC: 26365 AN: 152118 Hom.: 2398 Cov.: 33 AF XY: 0.173 AC XY: 12899 AN XY: 74366

Gnomad4 AFR AF: 0.214

Gnomad4 AMR AF: 0.123

Gnomad4 ASJ AF: 0.166

Gnomad4 EAS AF: 0.199

Gnomad4 SAS AF: 0.300

Gnomad4 FIN AF: 0.145

Gnomad4 NFE AF: 0.153

Gnomad4 OTH AF: 0.181

Alfa AF: 0.157 Hom.: 3058

Bravo AF: 0.171

Asia WGS AF: 0.246 AC: 859 AN: 3478

EpiCase AF: 0.159

EpiControl AF: 0.165

ClinVar

Significance: Benign

Submissions summary: Benign:15

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

- -

-

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

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

- -

-

PreventionGenetics, part of Exact Sciences

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

- -

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 02, 2025

ClinGen Lysosomal Storage Disorder Variant Curation Expert Panel

Significance: Benign

Review Status: reviewed by expert panel

Collection Method: curation

The NM_000203.5:c.543T>C variant in IDUA is a synonymous (silent) variant (p.Asn181=). The Grpmax Filtering AF (95% confidence) in gnomAD v4.1.0 is 0.2950 in the South Asian population. This 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: 92645). 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 January 2, 2025) -

May 11, 2017

Natera, Inc.

Significance: Benign

Review Status: no assertion criteria provided

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. -

not provided Benign:3

Jul 05, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 02, 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

- -

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
BayesDel_noAF	Benign	-0.66
CADD	Benign	0.60
DANN	Benign	0.63
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs6815946; hg19: chr4-995305; COSMIC: COSV56102644; COSMIC: COSV56102644;