rs73066479

Positions:

chr4-1002902-G-A

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.1360G>A variant in IDUA is a missense variant predicted to cause substitution of valine by isoleucine at amino acid 454 (p.Val454Ile). The highest population minor allele frequency in gnomAD v4.1.0 is 0.3004 (19925/66322 alleles; 3158 homozygotes; Grpmax Filtering AF 95% confidence = 0.2969) 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: 92630). 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/CA145872/MONDO:0001586/091

Frequency

Genomes: 𝑓 0.17 ( 2366 hom., cov: 33)

Exomes 𝑓: 0.16 ( 17534 hom. )

Consequence

IDUA
NM_000203.5 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 1.15

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.1360G>A	p.Val454Ile	missense_variant	9/14	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.1360G>A	p.Val454Ile	missense_variant	9/14	2	NM_000203.5	ENSP00000425081	P1	P35475-1

Frequencies

GnomAD3 genomes

AF:

0.173

AC:

26206

AN:

151822

Hom.:

2370

Cov.:

show subpopulations

Gnomad AFR

AF:

0.213

Gnomad AMI

AF:

0.171

Gnomad AMR

AF:

0.124

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:

0.183

GnomAD3 exomes

AF:

0.203

AC:

7144

AN:

35220

Hom.:

867

AF XY:

0.219

AC XY:

4701

AN XY:

21452

show subpopulations

Gnomad AFR exome

AF:

0.247

Gnomad AMR exome

AF:

0.0791

Gnomad ASJ exome

AF:

0.195

Gnomad EAS exome

AF:

0.255

Gnomad SAS exome

AF:

0.322

Gnomad FIN exome

AF:

0.169

Gnomad NFE exome

AF:

0.183

Gnomad OTH exome

AF:

0.203

GnomAD4 exome

AF:

0.161

AC:

202361

AN:

1256844

Hom.:

17534

Cov.:

AF XY:

0.164

AC XY:

101139

AN XY:

615192

show subpopulations

Gnomad4 AFR exome

AF:

0.222

Gnomad4 AMR exome

AF:

0.0948

Gnomad4 ASJ exome

AF:

0.164

Gnomad4 EAS exome

AF:

0.158

Gnomad4 SAS exome

AF:

0.301

Gnomad4 FIN exome

AF:

0.159

Gnomad4 NFE exome

AF:

0.152

Gnomad4 OTH exome

AF:

0.169

GnomAD4 genome

AF:

0.172

AC:

26203

AN:

151930

Hom.:

2366

Cov.:

AF XY:

0.173

AC XY:

12841

AN XY:

74290

show subpopulations

Gnomad4 AFR

AF:

0.212

Gnomad4 AMR

AF:

0.124

Gnomad4 ASJ

AF:

0.166

Gnomad4 EAS

AF:

0.201

Gnomad4 SAS

AF:

0.299

Gnomad4 FIN

AF:

0.144

Gnomad4 NFE

AF:

0.152

Gnomad4 OTH

AF:

0.182

Alfa

AF:

0.151

Hom.:

237

Bravo

AF:

0.170

TwinsUK

AF:

0.166

AC:

614

ALSPAC

AF:

0.159

AC:

614

ExAC

AF:

0.114

AC:

3158

Asia WGS

AF:

0.250

AC:

869

AN:

3462

ClinVar

Significance: Benign

Submissions summary: Benign:14

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:4

Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Nov 02, 2017	- -
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	-	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -

not provided

Benign:4

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Aug 29, 2018	This variant is associated with the following publications: (PMID: 12509712, 28649516) -
Benign, no assertion criteria provided	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Feb 27, 2017	- -

Mucopolysaccharidosis type 1

Benign:3

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. -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -

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

0.10

BayesDel_addAF

Benign

-0.52

BayesDel_noAF

Benign

-0.38

CADD

Benign

3.8

DANN

Benign

0.47

DEOGEN2

Uncertain

0.47

T;.

Eigen

Benign

-1.0

Eigen_PC

Benign

-1.1

FATHMM_MKL

Benign

0.039

LIST_S2

Benign

0.62

T;.

MetaRNN

Benign

0.0035

T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.85

L;.

MutationTaster

Benign

1.0

P;P;P

PrimateAI

Uncertain

0.72

PROVEAN

Benign

-0.17

N;N

REVEL

Benign

0.094

Sift

Benign

0.81

T;T

Sift4G

Benign

0.41

T;T

Polyphen

0.0070

B;.

Vest4

0.016

MPC

0.16

ClinPred

0.0022

GERP RS

0.14

Varity_R

0.13

gMVP

0.15

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