4-1002460-G-C

Variant names:

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.1164G>C (p.Thr388=) variant is a synonymous (silent) variant. The highest population minor allele frequency in gnomAD v4.1.0 is 0.2976 (25114/84382 alleles; 3978 homozygotes; Grpmax Filtering AF 95% confidence = 0.2945) 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: 92625). In summary, this variant meets the criteria to be classified as benign for MPS I based on the 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/CA145867/MONDO:0001586/091

Frequency

Genomes: 𝑓 0.17 ( 2368 hom., cov: 34)

Exomes 𝑓: 0.16 ( 19662 hom. )

Consequence

IDUA
NM_000203.5 synonymous

Scores

Clinical Significance

Benign reviewed by expert panel B:13

Conservation

PhyloP100: -6.27

Variant links:

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

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 link	c.1164G>C	p.Thr388Thr	synonymous_variant	Exon 8 of 14	ENST00000514224.2	NP_000194.2	P35475-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
IDUA	ENST00000514224.2 link	c.1164G>C	p.Thr388Thr	synonymous_variant	Exon 8 of 14	2	NM_000203.5	ENSP00000425081.2	P35475-1
IDUA	ENST00000247933.9 link	c.1164G>C	p.Thr388Thr	synonymous_variant	Exon 8 of 14	1		ENSP00000247933.4	P35475-1
IDUA	ENST00000514698.5 link	n.1271G>C		non_coding_transcript_exon_variant	Exon 5 of 11	5
IDUA	ENST00000652070.1 link	n.1220G>C		non_coding_transcript_exon_variant	Exon 7 of 13

Frequencies

GnomAD3 genomes

AF:

0.173

AC:

26241

AN:

152064

Hom.:

2372

Cov.:

show subpopulations

Gnomad AFR

AF:

0.213

Gnomad AMI

AF:

0.171

Gnomad AMR

AF:

0.123

Gnomad ASJ

AF:

0.166

Gnomad EAS

AF:

0.201

Gnomad SAS

AF:

0.300

Gnomad FIN

AF:

0.144

Gnomad MID

AF:

0.236

Gnomad NFE

AF:

0.152

Gnomad OTH

AF:

0.182

GnomAD3 exomes

AF:

0.174

AC:

26448

AN:

151750

Hom.:

2720

AF XY:

0.185

AC XY:

15043

AN XY:

81426

show subpopulations

Gnomad AFR exome

AF:

0.218

Gnomad AMR exome

AF:

0.0822

Gnomad ASJ exome

AF:

0.162

Gnomad EAS exome

AF:

0.215

Gnomad SAS exome

AF:

0.300

Gnomad FIN exome

AF:

0.144

Gnomad NFE exome

AF:

0.160

Gnomad OTH exome

AF:

0.176

GnomAD4 exome

AF:

0.161

AC:

225509

AN:

1398620

Hom.:

19662

Cov.:

AF XY:

0.165

AC XY:

113950

AN XY:

690122

show subpopulations

Gnomad4 AFR exome

AF:

0.222

Gnomad4 AMR exome

AF:

0.0884

Gnomad4 ASJ exome

AF:

0.161

Gnomad4 EAS exome

AF:

0.168

Gnomad4 SAS exome

AF:

0.297

Gnomad4 FIN exome

AF:

0.152

Gnomad4 NFE exome

AF:

0.151

Gnomad4 OTH exome

AF:

0.169

GnomAD4 genome

AF:

0.172

AC:

26238

AN:

152180

Hom.:

2368

Cov.:

AF XY:

0.173

AC XY:

12844

AN XY:

74382

show subpopulations

Gnomad4 AFR

AF:

0.212

Gnomad4 AMR

AF:

0.123

Gnomad4 ASJ

AF:

0.166

Gnomad4 EAS

AF:

0.201

Gnomad4 SAS

AF:

0.300

Gnomad4 FIN

AF:

0.144

Gnomad4 NFE

AF:

0.152

Gnomad4 OTH

AF:

0.181

Alfa

AF:

0.122

Hom.:

452

Bravo

AF:

0.170

Asia WGS

AF:

0.248

AC:

866

AN:

3474

ClinVar

Significance: Benign

Submissions summary: Benign:13

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

not specified

Benign:5

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

- -

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

- -

Mucopolysaccharidosis type 1

Benign:4

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. -

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.1164G>C (p.Thr388=) variant is a synonymous (silent) variant. The highest population minor allele frequency in gnomAD v4.1.0 is 0.2976 (25114/84382 alleles; 3978 homozygotes; Grpmax Filtering AF 95% confidence = 0.2945) 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: 92625). In summary, this variant meets the criteria to be classified as benign for MPS I based on the 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) -

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Aug 08, 2017

Natera, Inc.

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

not provided

Benign:4

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Aug 29, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 16438163, 28649516, 9391892, 12509712) -

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

- -

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

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.90

CADD

Benign

0.017

DANN

Benign

0.63

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over