4-1002131-G-C

Variant names:

• chr4-1002131-G-C
• rs6830825
• NM_000203.5:c.942G>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.942G>C variant in IDUA is a synonymous (silent) variant (p.Ala314=). The Grpmax Filtering AF (95% confidence) in gnomAD v4.1.0 is 0.2937 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: 92650). 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/CA145892/MONDO:0001586/091

• Frequency:
  • Genomes: 𝑓 0.17 (2352 hom., cov: 33)
  • Exomes 𝑓: 0.16 (19683 hom.)
• Consequence: IDUA NM_000203.5 synonymous
• Clinical Significance: Benign reviewed by expert panel B:15
• Conservation: PhyloP100: -4.78

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.942G>C	p.Ala314Ala	synonymous_variant	Exon 7 of 14	ENST00000514224.2	NP_000194.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
IDUA	ENST00000514224.2	c.942G>C	p.Ala314Ala	synonymous_variant	Exon 7 of 14	2	NM_000203.5	ENSP00000425081.2

Frequencies

GnomAD3 genomes AF: 0.172 AC: 26198 AN: 152082 Hom.: 2356 Cov.: 33

Gnomad AFR AF: 0.212

Gnomad AMI AF: 0.171

Gnomad AMR AF: 0.124

Gnomad ASJ AF: 0.165

Gnomad EAS AF: 0.200

Gnomad SAS AF: 0.299

Gnomad FIN AF: 0.143

Gnomad MID AF: 0.234

Gnomad NFE AF: 0.152

Gnomad OTH AF: 0.182

GnomAD3 exomes AF: 0.172 AC: 28962 AN: 168596 Hom.: 2858 AF XY: 0.181 AC XY: 16331 AN XY: 90280

Gnomad AFR exome AF: 0.215

Gnomad AMR exome AF: 0.0809

Gnomad ASJ exome AF: 0.161

Gnomad EAS exome AF: 0.209

Gnomad SAS exome AF: 0.297

Gnomad FIN exome AF: 0.144

Gnomad NFE exome AF: 0.157

Gnomad OTH exome AF: 0.173

GnomAD4 exome AF: 0.161 AC: 226832 AN: 1411856 Hom.: 19683 Cov.: 35 AF XY: 0.164 AC XY: 114702 AN XY: 697474

Gnomad4 AFR exome AF: 0.220

Gnomad4 AMR exome AF: 0.0868

Gnomad4 ASJ exome AF: 0.161

Gnomad4 EAS exome AF: 0.168

Gnomad4 SAS exome AF: 0.297

Gnomad4 FIN exome AF: 0.151

Gnomad4 NFE exome AF: 0.151

Gnomad4 OTH exome AF: 0.168

GnomAD4 genome AF: 0.172 AC: 26195 AN: 152200 Hom.: 2352 Cov.: 33 AF XY: 0.172 AC XY: 12811 AN XY: 74396

Gnomad4 AFR AF: 0.212

Gnomad4 AMR AF: 0.123

Gnomad4 ASJ AF: 0.165

Gnomad4 EAS AF: 0.199

Gnomad4 SAS AF: 0.299

Gnomad4 FIN AF: 0.143

Gnomad4 NFE AF: 0.152

Gnomad4 OTH AF: 0.181

Alfa AF: 0.153 Hom.: 625

Bravo AF: 0.169

Asia WGS AF: 0.249 AC: 871 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:15

Revision: reviewed by expert panel

Submissions by phenotype

not specified Benign:5

-

PreventionGenetics, part of Exact Sciences

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, Academic Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Dec 11, 2015

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

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

- -

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 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. -

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.942G>C variant in IDUA is a synonymous (silent) variant (p.Ala314=). The Grpmax Filtering AF (95% confidence) in gnomAD v4.1.0 is 0.2937 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: 92650). 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

- -

not provided Benign:3

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

- -

Feb 02, 2016

Mayo Clinic Laboratories, Mayo Clinic

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

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	-0.91
CADD	Benign	0.54
DANN	Benign	0.29
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

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: rs6830825; hg19: chr4-995919; COSMIC: COSV56102732; COSMIC: COSV56102732;