4-1002713-GCCC-GCCCC

Variant names:

• chr4-1002713-G-GC
• rs150523349
• NM_000203.5:c.1190-10dupC

Variant summary

Our verdict is Benign. Variant got -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
• Clinical Significance: Benign reviewed by expert panel B:10
• Conservation: PhyloP100: -0.792

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.1190-10dupC		intron_variant	Intron 8 of 13	ENST00000514224.2	NP_000194.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
IDUA	ENST00000514224.2	c.1190-19_1190-18insC		intron_variant	Intron 8 of 13	2	NM_000203.5	ENSP00000425081.2

Frequencies

GnomAD3 genomes AF: 0.164 AC: 24511 AN: 149414 Hom.: 2051 Cov.: 29

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

GnomAD3 exomes AF: 0.160 AC: 11726 AN: 73188 Hom.: 595 AF XY: 0.174 AC XY: 7220 AN XY: 41468

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 SAS exome AF: 0.266

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.: 24 AF XY: 0.0998 AC XY: 58876 AN XY: 590056

Gnomad4 AFR exome AF: 0.118

Gnomad4 AMR exome AF: 0.0725

Gnomad4 ASJ exome AF: 0.127

Gnomad4 EAS exome AF: 0.126

Gnomad4 SAS exome AF: 0.231

Gnomad4 FIN exome AF: 0.141

Gnomad4 NFE exome AF: 0.0784

Gnomad4 OTH exome AF: 0.106

GnomAD4 genome AF: 0.164 AC: 24506 AN: 149514 Hom.: 2046 Cov.: 29 AF XY: 0.164 AC XY: 11960 AN XY: 72964

Gnomad4 AFR AF: 0.192

Gnomad4 AMR AF: 0.121

Gnomad4 ASJ AF: 0.167

Gnomad4 EAS AF: 0.192

Gnomad4 SAS AF: 0.296

Gnomad4 FIN AF: 0.136

Gnomad4 NFE AF: 0.149

Gnomad4 OTH AF: 0.174

ClinVar

Significance: Benign

Submissions summary: Benign:10

Revision: reviewed by expert panel

Submissions by phenotype

not specified Benign:4

-

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

- -

Jul 17, 2012

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Mucopolysaccharidosis type 1 Benign:3

Feb 03, 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

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) -

Sep 16, 2020

Natera, Inc.

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

not provided Benign:3

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

Variant summary: The c.1190-10dupC variant affects a intronic polyC site. One in-silico tool predicts benign outcome for this variant. 5/5 programs in Alamut predict that this variant does not affect normal splicing. This variant is found in 1655/7502 control chromosomes (116 homozygotes) at a frequency of 0.2206078, which is about 82 times of maximal expected frequency of a pathogenic allele (0.0026926), suggesting this variant is benign. In addition, one clinical laboratory classified this variant as bengin. Taken together, this variant was classified as benign. -

Sep 17, 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

- -

Computational scores

Source: dbNSFP v4.3

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: rs150523349; hg19: chr4-996501;