4-1003100-C-T

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_000203.5(IDUA):c.1467C>T(p.Arg489=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.162 in 1,514,776 control chromosomes in the GnomAD database, including 21,380 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. R489R) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.17 ( 2355 hom., cov: 33)

Exomes 𝑓: 0.16 ( 19025 hom. )

Consequence

IDUA
NM_000203.5 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:11

Conservation

PhyloP100: -0.905

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 -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.74).

BP6

Variant 4-1003100-C-T is Benign according to our data. Variant chr4-1003100-C-T is described in ClinVar as [Benign]. Clinvar id is 92632.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr4-1003100-C-T is described in Lovd as [Benign].

BP7

Synonymous conserved (PhyloP=-0.905 with no splicing effect.

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.286 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
IDUA	NM_000203.5 linkuse as main transcript	c.1467C>T	p.Arg489=	synonymous_variant	10/14	ENST00000514224.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
IDUA	ENST00000514224.2 linkuse as main transcript	c.1467C>T	p.Arg489=	synonymous_variant	10/14	2	NM_000203.5	P1	P35475-1

Frequencies

GnomAD3 genomes

AF:

0.172

AC:

26134

AN:

151710

Hom.:

2359

Cov.:

show subpopulations

Gnomad AFR

AF:

0.212

Gnomad AMI

AF:

0.170

Gnomad AMR

AF:

0.124

Gnomad ASJ

AF:

0.165

Gnomad EAS

AF:

0.201

Gnomad SAS

AF:

0.299

Gnomad FIN

AF:

0.144

Gnomad MID

AF:

0.236

Gnomad NFE

AF:

0.152

Gnomad OTH

AF:

0.183

GnomAD3 exomes

AF:

0.174

AC:

25755

AN:

148148

Hom.:

2596

AF XY:

0.186

AC XY:

15807

AN XY:

85208

show subpopulations

Gnomad AFR exome

AF:

0.220

Gnomad AMR exome

AF:

0.0699

Gnomad ASJ exome

AF:

0.159

Gnomad EAS exome

AF:

0.216

Gnomad SAS exome

AF:

0.295

Gnomad FIN exome

AF:

0.157

Gnomad NFE exome

AF:

0.163

Gnomad OTH exome

AF:

0.175

GnomAD4 exome

AF:

0.161

AC:

218886

AN:

1362958

Hom.:

19025

Cov.:

AF XY:

0.165

AC XY:

111298

AN XY:

676220

show subpopulations

Gnomad4 AFR exome

AF:

0.220

Gnomad4 AMR exome

AF:

0.0799

Gnomad4 ASJ exome

AF:

0.160

Gnomad4 EAS exome

AF:

0.162

Gnomad4 SAS exome

AF:

0.295

Gnomad4 FIN exome

AF:

0.158

Gnomad4 NFE exome

AF:

0.152

Gnomad4 OTH exome

AF:

0.167

GnomAD4 genome

AF:

0.172

AC:

26131

AN:

151818

Hom.:

2355

Cov.:

AF XY:

0.172

AC XY:

12796

AN XY:

74224

show subpopulations

Gnomad4 AFR

AF:

0.212

Gnomad4 AMR

AF:

0.123

Gnomad4 ASJ

AF:

0.165

Gnomad4 EAS

AF:

0.200

Gnomad4 SAS

AF:

0.298

Gnomad4 FIN

AF:

0.144

Gnomad4 NFE

AF:

0.152

Gnomad4 OTH

AF:

0.182

Alfa

AF:

0.151

Hom.:

236

Bravo

AF:

0.169

Asia WGS

AF:

0.248

AC:

861

AN:

3450

ClinVar

Significance: Benign

Submissions summary: Benign:11

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:5

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

Mucopolysaccharidosis type 1

Benign:3

Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -
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. -
Benign, no assertion criteria provided	clinical testing	Natera, Inc.	May 11, 2017	- -

not provided

Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 05, 2018	- -
Benign, no assertion criteria provided	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Jan 29, 2016	- -

Hurler syndrome

Benign:1

Benign, criteria provided, single submitter

clinical testing

Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center

Apr 04, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.74

Cadd

Benign

6.4

Dann

Benign

0.88

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

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