rs3755955

Positions:

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.314G>A variant in IDUA is a missense variant predicted to cause substitution of arginine by glutamine at amino acid 105 (p.Arg105Gln). The highest population minor allele frequency in gnomAD v4.1.0 is 0.2431 (22127/91024 alleles; 2838 homozygotes; Grpmax Filtering AF 95% confidence = 0.2404) 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: 92641). 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/CA145881/MONDO:0001586/091

Frequency

Genomes: 𝑓 0.14 ( 1595 hom., cov: 34)

Exomes 𝑓: 0.15 ( 18412 hom. )

Consequence

IDUA
NM_000203.5 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:16

Conservation

PhyloP100: 0.235

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/exons	MANE	Protein	UniProt
IDUA	NM_000203.5 linkuse as main transcript	c.314G>A	p.Arg105Gln	missense_variant	3/14	ENST00000514224.2	NP_000194.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
IDUA	ENST00000514224.2 linkuse as main transcript	c.314G>A	p.Arg105Gln	missense_variant	3/14	2	NM_000203.5	ENSP00000425081	P1	P35475-1

Frequencies

GnomAD3 genomes

AF:

0.142

AC:

21587

AN:

152130

Hom.:

1599

Cov.:

show subpopulations

Gnomad AFR

AF:

0.116

Gnomad AMI

AF:

0.171

Gnomad AMR

AF:

0.107

Gnomad ASJ

AF:

0.164

Gnomad EAS

AF:

0.193

Gnomad SAS

AF:

0.242

Gnomad FIN

AF:

0.144

Gnomad MID

AF:

0.225

Gnomad NFE

AF:

0.152

Gnomad OTH

AF:

0.150

GnomAD3 exomes

AF:

0.157

AC:

39334

AN:

250258

Hom.:

3421

AF XY:

0.165

AC XY:

22390

AN XY:

135698

show subpopulations

Gnomad AFR exome

AF:

0.117

Gnomad AMR exome

AF:

0.0721

Gnomad ASJ exome

AF:

0.157

Gnomad EAS exome

AF:

0.211

Gnomad SAS exome

AF:

0.242

Gnomad FIN exome

AF:

0.147

Gnomad NFE exome

AF:

0.159

Gnomad OTH exome

AF:

0.162

GnomAD4 exome

AF:

0.154

AC:

225302

AN:

1458656

Hom.:

18412

Cov.:

AF XY:

0.157

AC XY:

114263

AN XY:

725732

show subpopulations

Gnomad4 AFR exome

AF:

0.116

Gnomad4 AMR exome

AF:

0.0760

Gnomad4 ASJ exome

AF:

0.157

Gnomad4 EAS exome

AF:

0.158

Gnomad4 SAS exome

AF:

0.243

Gnomad4 FIN exome

AF:

0.152

Gnomad4 NFE exome

AF:

0.152

Gnomad4 OTH exome

AF:

0.155

GnomAD4 genome

AF:

0.142

AC:

21578

AN:

152248

Hom.:

1595

Cov.:

AF XY:

0.142

AC XY:

10588

AN XY:

74438

show subpopulations

Gnomad4 AFR

AF:

0.116

Gnomad4 AMR

AF:

0.107

Gnomad4 ASJ

AF:

0.164

Gnomad4 EAS

AF:

0.192

Gnomad4 SAS

AF:

0.243

Gnomad4 FIN

AF:

0.144

Gnomad4 NFE

AF:

0.152

Gnomad4 OTH

AF:

0.147

Alfa

AF:

0.150

Hom.:

3602

Bravo

AF:

0.136

TwinsUK

AF:

0.165

AC:

612

ALSPAC

AF:

0.159

AC:

611

ESP6500AA

AF:

0.107

AC:

473

ESP6500EA

AF:

0.160

AC:

1376

ExAC

AF:

0.163

AC:

19766

Asia WGS

AF:

0.194

AC:

679

AN:

3478

EpiCase

AF:

0.157

EpiControl

AF:

0.163

ClinVar

Significance: Benign

Submissions summary: Benign:16

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 DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
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, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -

not provided

Benign:5

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, no assertion criteria provided	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Feb 03, 2016	- -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jan 15, 2016	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 05, 2018	This variant is associated with the following publications: (PMID: 31473686, 26256109, 21462124, 19396826, 9536518, 21639919, 24053568, 24875751) -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 29, 2023	- -

Mucopolysaccharidosis type 1

Benign:3

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. -
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	- -

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

AlphaMissense

Benign

0.067

BayesDel_addAF

Benign

-0.46

BayesDel_noAF

Benign

-0.29

CADD

Benign

0.74

DANN

Benign

0.77

DEOGEN2

Uncertain

0.46

T;.;T;T

Eigen

Benign

-1.6

Eigen_PC

Benign

-1.5

FATHMM_MKL

Benign

0.035

LIST_S2

Benign

0.41

T;T;.;.

MetaRNN

Benign

0.0045

T;T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

-0.91

N;.;.;.

MutationTaster

Benign

1.0

P;P;P

PrimateAI

Benign

0.20

PROVEAN

Benign

0.050

N;N;N;N

REVEL

Uncertain

0.32

Sift

Benign

1.0

T;T;T;T

Sift4G

Benign

0.72

T;T;T;T

Polyphen

0.0030

B;.;.;.

Vest4

0.019

MPC

0.22

ClinPred

0.000033

GERP RS

1.5

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.056

gMVP

0.55

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

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