4-1002772-C-G

Position:

• chr4-1002772-C-G

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.1230C>G variant in IDUA is a synonymous (silent) variant (p.Thr410=). The Grpmax Filtering AF (95% confidence) in gnomAD v4.1.0 is 0.2954 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: 92628). 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: BA1.(Classification approved by the ClinGen Lysosomal Diseases Variant Curation Expert Panel on January 2, 2025) LINK:https://erepo.genome.network/evrepo/ui/classification/CA145870/MONDO:0001586/091

• Frequency:
  • Genomes: 𝑓 0.17 (2327 hom., cov: 32)
  • Exomes 𝑓: 0.16 (18473 hom.)
• Consequence: IDUA NM_000203.5 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: -1.80

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 (HGNC:):

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/exons	MANE	Protein	UniProt
IDUA	NM_000203.5	c.1230C>G	p.Thr410Thr	synonymous_variant	9/14	ENST00000514224.2	NP_000194.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
IDUA	ENST00000514224.2	c.1230C>G	p.Thr410Thr	synonymous_variant	9/14	2	NM_000203.5	ENSP00000425081.2

Frequencies

GnomAD3 genomes AF: 0.172 AC: 25972 AN: 151430 Hom.: 2331 Cov.: 32

Gnomad AFR AF: 0.211

Gnomad AMI AF: 0.171

Gnomad AMR AF: 0.123

Gnomad ASJ AF: 0.166

Gnomad EAS AF: 0.199

Gnomad SAS AF: 0.302

Gnomad FIN AF: 0.142

Gnomad MID AF: 0.236

Gnomad NFE AF: 0.152

Gnomad OTH AF: 0.182

GnomAD3 exomes AF: 0.174 AC: 14580 AN: 83954 Hom.: 1556 AF XY: 0.190 AC XY: 9085 AN XY: 47820

Gnomad AFR exome AF: 0.208

Gnomad AMR exome AF: 0.0740

Gnomad ASJ exome AF: 0.161

Gnomad EAS exome AF: 0.221

Gnomad SAS exome AF: 0.296

Gnomad FIN exome AF: 0.156

Gnomad NFE exome AF: 0.158

Gnomad OTH exome AF: 0.174

GnomAD4 exome AF: 0.161 AC: 212281 AN: 1321686 Hom.: 18473 Cov.: 36 AF XY: 0.165 AC XY: 107188 AN XY: 651162

Gnomad4 AFR exome AF: 0.220

Gnomad4 AMR exome AF: 0.0863

Gnomad4 ASJ exome AF: 0.160

Gnomad4 EAS exome AF: 0.160

Gnomad4 SAS exome AF: 0.298

Gnomad4 FIN exome AF: 0.158

Gnomad4 NFE exome AF: 0.151

Gnomad4 OTH exome AF: 0.168

GnomAD4 genome AF: 0.171 AC: 25969 AN: 151538 Hom.: 2327 Cov.: 32 AF XY: 0.172 AC XY: 12705 AN XY: 74072

Gnomad4 AFR AF: 0.210

Gnomad4 AMR AF: 0.123

Gnomad4 ASJ AF: 0.166

Gnomad4 EAS AF: 0.199

Gnomad4 SAS AF: 0.301

Gnomad4 FIN AF: 0.142

Gnomad4 NFE AF: 0.152

Gnomad4 OTH AF: 0.181

Alfa AF: 0.0617 Hom.: 73

Bravo AF: 0.169

Asia WGS AF: 0.249 AC: 865 AN: 3452

ClinVar

Significance: Benign

Submissions summary: Benign:11

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Nov 02, 2017	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -

not provided Benign:4

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Aug 29, 2018	This variant is associated with the following publications: (PMID: 16438163, 28649516) -
Likely benign, no assertion criteria provided	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Dec 16, 2015	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -

Mucopolysaccharidosis type 1 Benign:3

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 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, no assertion criteria provided	clinical testing	Natera, Inc.	May 11, 2017	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.79
CADD	Benign	1.6
DANN	Benign	0.50

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs115790973; hg19: chr4-996560;