chr4-1002767-G-C

Variant names:

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_StrongBP6BA1

The NM_000203.5(IDUA):c.1225G>C(p.Gly409Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00371 in 1,481,578 control chromosomes in the GnomAD database, including 125 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.018 ( 72 hom., cov: 33)

Exomes 𝑓: 0.0020 ( 53 hom. )

Consequence

IDUA
NM_000203.5 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:11

Conservation

PhyloP100: 0.768

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 -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.030357838).

BP6

Variant 4-1002767-G-C is Benign according to our data. Variant chr4-1002767-G-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 92627.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=3, Benign=5, Uncertain_significance=1}. Variant chr4-1002767-G-C is described in Lovd as [Likely_benign]. Variant chr4-1002767-G-C is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0573 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
IDUA	NM_000203.5 link	c.1225G>C	p.Gly409Arg	missense_variant	Exon 9 of 14	ENST00000514224.2	NP_000194.2	P35475-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
IDUA	ENST00000514224.2 link	c.1225G>C	p.Gly409Arg	missense_variant	Exon 9 of 14	2	NM_000203.5	ENSP00000425081.2		P35475-1

Frequencies

GnomAD3 genomes

AF:

0.0183

AC:

2757

AN:

150922

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0589

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0106

Gnomad ASJ

AF:

0.00924

Gnomad EAS

AF:

0.0163

Gnomad SAS

AF:

0.00105

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00974

Gnomad NFE

AF:

0.000487

Gnomad OTH

AF:

0.0129

GnomAD3 exomes

AF:

0.00358

AC:

313

AN:

87312

Hom.:

AF XY:

0.00261

AC XY:

129

AN XY:

49498

show subpopulations

Gnomad AFR exome

AF:

0.0560

Gnomad AMR exome

AF:

0.00509

Gnomad ASJ exome

AF:

0.00813

Gnomad EAS exome

AF:

0.0148

Gnomad SAS exome

AF:

0.000116

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000714

Gnomad OTH exome

AF:

0.00429

GnomAD4 exome

AF:

0.00204

AC:

2720

AN:

1330546

Hom.:

Cov.:

AF XY:

0.00176

AC XY:

1155

AN XY:

655764

show subpopulations

Gnomad4 AFR exome

AF:

0.0561

Gnomad4 AMR exome

AF:

0.00509

Gnomad4 ASJ exome

AF:

0.00700

Gnomad4 EAS exome

AF:

0.0103

Gnomad4 SAS exome

AF:

0.000137

Gnomad4 FIN exome

AF:

0.0000299

Gnomad4 NFE exome

AF:

0.000230

Gnomad4 OTH exome

AF:

0.00586

GnomAD4 genome

AF:

0.0184

AC:

2775

AN:

151032

Hom.:

Cov.:

AF XY:

0.0175

AC XY:

1292

AN XY:

73836

show subpopulations

Gnomad4 AFR

AF:

0.0593

Gnomad4 AMR

AF:

0.0106

Gnomad4 ASJ

AF:

0.00924

Gnomad4 EAS

AF:

0.0163

Gnomad4 SAS

AF:

0.000839

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000487

Gnomad4 OTH

AF:

0.0128

Alfa

AF:

0.00175

Hom.:

Bravo

AF:

0.0206

ESP6500AA

AF:

0.0278

AC:

ESP6500EA

AF:

0.000437

AC:

ExAC

AF:

0.00388

AC:

Asia WGS

AF:

0.00785

AC:

AN:

3452

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2Benign:11

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not specified

Uncertain:1Benign:3

Jun 08, 2015

Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 07, 2022

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: IDUA c.1225G>C (p.Gly409Arg) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.0072 in 118354 control chromosomes (gnomAD), predominantly at a frequency of 0.057 within the African or African-American subpopulation in the gnomAD database, including 16 homozygotes. The observed variant frequency within African or African-American control individuals in the gnomAD database is approximately 21 fold of the estimated maximal expected allele frequency for a pathogenic variant in IDUA causing Mucopolysaccharidosis Type 1 (0.0027), strongly suggesting that the variant is a benign polymorphism found primarily in populations of African or African-American origin. Nine ClinVar submitters have assessed the variant since 2014: two classified the variant as of uncertain significance, three as likely benign, and four as benign. Based on the evidence outlined above, the variant was classified as benign. -

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Mar 09, 2015

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mucopolysaccharidosis type 1

Benign:4

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

Jan 13, 2020

Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: curation

The p.Gly409Arg variant has not been previously reported in individuals with mucopolysaccharidosis (MPS) but has been identified in 5.567% (555/9810) of African chromosomes, including 16 homozygotes, and 3 additional homozygotes in other populations, by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs11934801). This variant has been seen in the general population at a frequency high enough to rule out a pathogenic role. This variant has also been reported in ClinVar as benign by Invitae, EGL Genetic Diagnostics, and Children's Mercy Hospital and Clinics, likely benign by Illumina, and a VUS by the Children's Hospital of Philadelphia and the NUS Institute of Precision Medicine (Variation ID: 92627). It has also been reported in the heterozygous state and described as a pseudodeficiency allele in an unaffected individual from newborn screening, suggesting that this variant is not pathogenic for disease (PMID: 31133280). In summary, this variant meets criteria to be classified as benign for mucopolysaccharidosis in an autosomal recessive manner based on the high frequency of the variant in the general population. ACMG/AMP Criteria applied: BA1, BS2 (Richards 2015). -

Feb 02, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Apr 23, 2020

Natera, Inc.

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

not provided

Benign:3

Dec 04, 2020

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Appears to be a hypomorphic allele. Functional studies indicate that this variant reduces protein activity to 61% (Bach et al., 1993), which is not in the pathogenic range for this enzyme.; This variant is associated with the following publications: (PMID: 30709774, 31133280, 28676128, 27335677, 8328452, 21228398) -

Clinical Genetics, Academic Medical Center

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Sep 08, 2016

Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Hurler syndrome

Uncertain:1Benign:1

Jun 07, 2017

SingHealth Duke-NUS Institute of Precision Medicine

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: curation

- -

May 28, 2019

Mendelics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.18

BayesDel_addAF

Benign

-0.23

BayesDel_noAF

Uncertain

-0.060

CADD

Benign

DANN

Benign

0.93

DEOGEN2

Pathogenic

0.83

D;.

Eigen

Benign

-0.085

Eigen_PC

Benign

-0.25

FATHMM_MKL

Benign

0.54

LIST_S2

Benign

0.72

T;.

MetaRNN

Benign

0.030

T;T

MetaSVM

Uncertain

0.16

MutationAssessor

Benign

1.6

L;.

PrimateAI

Pathogenic

0.82

PROVEAN

Uncertain

-2.8

D;D

REVEL

Uncertain

0.47

Sift

Benign

0.088

T;T

Sift4G

Benign

0.12

T;T

Polyphen

0.95

P;.

Vest4

0.24

MVP

0.99

MPC

0.32

ClinPred

0.027

GERP RS

2.7

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.26

gMVP

0.59

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