chr4-1002131-G-C

Position:

chr4-1002131-G-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

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:14

Conservation

PhyloP100: -4.78

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:

IDUA (HGNC:):

IDUA links:

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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/exons	MANE	Protein	UniProt
IDUA	NM_000203.5 linkuse as main transcript	c.942G>C	p.Ala314Ala	synonymous_variant	7/14	ENST00000514224.2	NP_000194.2	P35475-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
IDUA	ENST00000514224.2 linkuse as main transcript	c.942G>C	p.Ala314Ala	synonymous_variant	7/14	2	NM_000203.5	ENSP00000425081.2	P35475-1
IDUA	ENST00000247933.9 linkuse as main transcript	c.942G>C	p.Ala314Ala	synonymous_variant	7/14	1		ENSP00000247933.4	P35475-1
IDUA	ENST00000514698.5 linkuse as main transcript	n.942G>C		non_coding_transcript_exon_variant	5/11	5
IDUA	ENST00000652070.1 linkuse as main transcript	n.998G>C		non_coding_transcript_exon_variant	6/13

Frequencies

GnomAD3 genomes

AF:

0.172

AC:

26198

AN:

152082

Hom.:

2356

Cov.:

show subpopulations

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

show subpopulations

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.:

AF XY:

0.164

AC XY:

114702

AN XY:

697474

show subpopulations

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.:

AF XY:

0.172

AC XY:

12811

AN XY:

74396

show subpopulations

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:14

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:5

Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Dec 11, 2015	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -

Mucopolysaccharidosis type 1

Benign:3

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	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 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. -

not provided

Benign:3

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, no assertion criteria provided	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Feb 02, 2016	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 05, 2018	- -

Mucopolysaccharidosis, MPS-I-H/S

Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 10, 2021

- -

Mucopolysaccharidosis, MPS-I-S

Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 10, 2021

- -

Hurler syndrome

Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 10, 2021

- -

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

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