rs6831280

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.1081G>A variant in IDUA is a missense variant predicted to cause substitution of alanine by threonine at amino acid 361 (p.Ala361Thr). The highest population minor allele frequency in gnomAD v4.1.0 is 0.2976 (27037/90842 alleles; 4256 homozygotes; Grpmax Filtering AF 95% confidence = 0.2947) 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: 92624). 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/CA145865/MONDO:0001586/091

Frequency

Genomes: 𝑓 0.17 ( 2341 hom., cov: 34)

Exomes 𝑓: 0.16 ( 20394 hom. )

Consequence

IDUA
NM_000203.5 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:13O:1

Conservation

PhyloP100: 1.14

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.1081G>A	p.Ala361Thr	missense_variant	8/14	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.1081G>A	p.Ala361Thr	missense_variant	8/14	2	NM_000203.5	ENSP00000425081	P1	P35475-1
IDUA	ENST00000247933.9 linkuse as main transcript	c.1081G>A	p.Ala361Thr	missense_variant	8/14	1		ENSP00000247933	P1	P35475-1
IDUA	ENST00000514698.5 linkuse as main transcript	n.1188G>A		non_coding_transcript_exon_variant	5/11	5
IDUA	ENST00000652070.1 linkuse as main transcript	n.1137G>A		non_coding_transcript_exon_variant	7/13

Frequencies

GnomAD3 genomes

AF:

0.172

AC:

26116

AN:

152110

Hom.:

2344

Cov.:

show subpopulations

Gnomad AFR

AF:

0.212

Gnomad AMI

AF:

0.169

Gnomad AMR

AF:

0.122

Gnomad ASJ

AF:

0.160

Gnomad EAS

AF:

0.200

Gnomad SAS

AF:

0.299

Gnomad FIN

AF:

0.144

Gnomad MID

AF:

0.228

Gnomad NFE

AF:

0.152

Gnomad OTH

AF:

0.179

GnomAD3 exomes

AF:

0.172

AC:

41988

AN:

243470

Hom.:

4099

AF XY:

0.181

AC XY:

23973

AN XY:

132448

show subpopulations

Gnomad AFR exome

AF:

0.218

Gnomad AMR exome

AF:

0.0782

Gnomad ASJ exome

AF:

0.154

Gnomad EAS exome

AF:

0.214

Gnomad SAS exome

AF:

0.300

Gnomad FIN exome

AF:

0.147

Gnomad NFE exome

AF:

0.160

Gnomad OTH exome

AF:

0.173

GnomAD4 exome

AF:

0.161

AC:

234399

AN:

1458830

Hom.:

20394

Cov.:

AF XY:

0.165

AC XY:

119589

AN XY:

725586

show subpopulations

Gnomad4 AFR exome

AF:

0.220

Gnomad4 AMR exome

AF:

0.0834

Gnomad4 ASJ exome

AF:

0.153

Gnomad4 EAS exome

AF:

0.171

Gnomad4 SAS exome

AF:

0.298

Gnomad4 FIN exome

AF:

0.152

Gnomad4 NFE exome

AF:

0.151

Gnomad4 OTH exome

AF:

0.167

GnomAD4 genome

AF:

0.172

AC:

26114

AN:

152224

Hom.:

2341

Cov.:

AF XY:

0.172

AC XY:

12793

AN XY:

74430

show subpopulations

Gnomad4 AFR

AF:

0.212

Gnomad4 AMR

AF:

0.122

Gnomad4 ASJ

AF:

0.160

Gnomad4 EAS

AF:

0.200

Gnomad4 SAS

AF:

0.299

Gnomad4 FIN

AF:

0.144

Gnomad4 NFE

AF:

0.152

Gnomad4 OTH

AF:

0.178

Alfa

AF:

0.158

Hom.:

2117

Bravo

AF:

0.168

TwinsUK

AF:

0.166

AC:

614

ALSPAC

AF:

0.159

AC:

611

ESP6500AA

AF:

0.200

AC:

880

ESP6500EA

AF:

0.158

AC:

1360

ExAC

AF:

0.179

AC:

21632

Asia WGS

AF:

0.248

AC:

868

AN:

3476

ClinVar

Significance: Benign

Submissions summary: Benign:13Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:6

Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
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	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)	Nov 02, 2017	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

Mucopolysaccharidosis type 1

Benign:3Other:1

Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Mar 29, 2017	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
not provided, no classification provided	literature only	GeneReviews	-	Pseudodeficiency variants -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 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	clinical testing	GeneDx	Aug 29, 2018	This variant is associated with the following publications: (PMID: 28649516, 29801497, 26256109, 27884173, 24875751) -
Benign, no assertion criteria provided	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Jan 29, 2016	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Hurler syndrome

Benign:1

Benign, criteria provided, single submitter

clinical testing

Pars Genome Lab

May 18, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.067

BayesDel_addAF

Benign

-0.54

BayesDel_noAF

Benign

-0.41

CADD

Benign

0.94

DANN

Benign

0.83

DEOGEN2

Uncertain

0.46

T;.

Eigen

Benign

-1.5

Eigen_PC

Benign

-1.4

FATHMM_MKL

Benign

0.52

LIST_S2

Benign

0.81

T;.

MetaRNN

Benign

0.0061

T;T

MetaSVM

Benign

-0.88

MutationAssessor

Benign

-1.2

N;.

MutationTaster

Benign

1.0

P;P;P

PrimateAI

Uncertain

0.49

PROVEAN

Benign

1.3

N;N

REVEL

Benign

0.24

Sift

Benign

1.0

T;T

Sift4G

Benign

1.0

T;T

Polyphen

0.0040

B;.

Vest4

0.037

MPC

0.18

ClinPred

0.0033

GERP RS

-6.4

Varity_R

0.066

gMVP

0.38

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