chr4-1001756-G-A

Variant names:

Variant summary

Our verdict is Benign. The variant received -17 ACMG points: 3P and 20B. PM1PP3BP4_StrongBP6_Very_StrongBS1BS2

The NM_000203.5(IDUA):c.667G>A(p.Asp223Asn) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000331 in 1,598,148 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign,other (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D223E) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0020 ( 3 hom., cov: 34)

Exomes 𝑓: 0.00016 ( 0 hom. )

Consequence

IDUA
NM_000203.5 missense

Scores

Clinical Significance

Benign/Likely benign; other criteria provided, multiple submitters, no conflicts U:1B:3O:2

Conservation

PhyloP100: 9.68

Publications

14 publications found

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 Gene-Disease associations (from GenCC):

mucopolysaccharidosis type 1
Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen, Myriad Women’s Health
Scheie syndrome
Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Genomics England PanelApp, G2P, Labcorp Genetics (formerly Invitae), Orphanet
Hurler syndrome
Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Orphanet, Genomics England PanelApp, PanelApp Australia
Hurler-Scheie syndrome
Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Genomics England PanelApp, Orphanet

IDUA links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -17 ACMG points.

PM1

In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 10 uncertain in NM_000203.5

PP3

Multiple lines of computational evidence support a deleterious effect 7: AlphaMissense, Cadd, Eigen, M_CAP, phyloP100way_vertebrate, REVEL, REVEL [when BayesDel_addAF, max_spliceai, FATHMM_MKL, MetaRNN, MutationTaster was below the threshold]

BP4

Computational evidence support a benign effect (MetaRNN=0.020062923).

BP6

Variant 4-1001756-G-A is Benign according to our data. Variant chr4-1001756-G-A is described in ClinVar as Benign/Likely_benign|other. ClinVar VariationId is 426817.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00199 (303/152122) while in subpopulation AFR AF = 0.00696 (289/41508). AF 95% confidence interval is 0.0063. There are 3 homozygotes in GnomAd4. There are 152 alleles in the male GnomAd4 subpopulation. Median coverage is 34. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 3 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein
IDUA	NM_000203.5 link	c.667G>A	p.Asp223Asn	missense_variant	Exon 6 of 14	ENST00000514224.2	NP_000194.2
IDUA	NM_001363576.1 link	c.271G>A	p.Asp91Asn	missense_variant	Exon 5 of 13		NP_001350505.1
IDUA	XM_047415650.1 link	c.667G>A	p.Asp223Asn	missense_variant	Exon 6 of 12		XP_047271606.1
IDUA	NR_110313.1 link	n.755G>A		non_coding_transcript_exon_variant	Exon 6 of 14

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
IDUA	ENST00000514224.2 link	c.667G>A	p.Asp223Asn	missense_variant	Exon 6 of 14	2	NM_000203.5	ENSP00000425081.2

Frequencies

GnomAD3 genomes

AF:

0.00199

AC:

303

AN:

152004

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00698

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000916

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000363

AC:

AN:

220268

AF XY:

0.000238

show subpopulations

Gnomad AFR exome

AF:

0.00557

Gnomad AMR exome

AF:

0.000181

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000100

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000156

AC:

226

AN:

1446026

Hom.:

Cov.:

AF XY:

0.000145

AC XY:

104

AN XY:

719450

show subpopulations

African (AFR)

AF:

0.00573

AC:

191

AN:

33342

American (AMR)

AF:

0.000250

AC:

AN:

43946

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25976

East Asian (EAS)

AF:

0.00

AC:

AN:

39214

South Asian (SAS)

AF:

0.00

AC:

AN:

85596

European-Finnish (FIN)

AF:

0.00

AC:

AN:

42970

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5748

European-Non Finnish (NFE)

AF:

0.00000270

AC:

AN:

1109318

Other (OTH)

AF:

0.000350

AC:

AN:

59916

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.497

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00199

AC:

303

AN:

152122

Hom.:

Cov.:

AF XY:

0.00204

AC XY:

152

AN XY:

74366

show subpopulations

African (AFR)

AF:

0.00696

AC:

289

AN:

41508

American (AMR)

AF:

0.000915

AC:

AN:

15298

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5138

South Asian (SAS)

AF:

0.00

AC:

AN:

4806

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10612

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

67968

Other (OTH)

AF:

0.00

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.498

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00110

Hom.:

Bravo

AF:

0.00201

ESP6500AA

AF:

0.00529

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.000442

AC:

ClinVar

Significance: Benign/Likely benign; other

Submissions summary: Uncertain:1Benign:3Other:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Mucopolysaccharidosis type 1

Benign:1Other:2

Dec 19, 2018

Labcorp Genetics (formerly Invitae), Labcorp

Significance:other

Review Status:criteria provided, single submitter

Collection Method:clinical testing

pseudodeficiency allele

Apr 23, 2020

Natera, Inc.

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

GeneReviews

Significance:not provided

Review Status:no classification provided

Collection Method:literature only

Pseudodeficiency variants

not provided

Uncertain:1Benign:1

May 16, 2017

Mayo Clinic Laboratories, Mayo Clinic

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:clinical testing

Sep 28, 2018

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is associated with the following publications: (PMID: 27939258, 27238910)

Inborn genetic diseases

Benign:1

Nov 19, 2021

Ambry Genetics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.64

BayesDel_addAF

Benign

-0.17

BayesDel_noAF

Uncertain

-0.020

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.79

D;.;D;D;.

Eigen

Pathogenic

0.68

Eigen_PC

Uncertain

0.61

LIST_S2

Uncertain

0.96

D;D;.;.;.

M_CAP

Pathogenic

0.54

MetaRNN

Benign

0.020

T;T;T;T;T

MetaSVM

Uncertain

0.75

MutationAssessor

Uncertain

2.6

M;.;.;.;.

PhyloP100

9.7

PrimateAI

Uncertain

0.58

PROVEAN

Uncertain

-3.0

D;D;D;D;D

Sift

Benign

0.26

T;T;T;T;T

Sift4G

Benign

0.12

T;T;T;T;T

Vest4

0.77

ClinPred

0.098

GERP RS

5.4

Varity_R

0.73

gMVP

0.92

Mutation Taster

=89/11

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over