chr4-1002224-G-C

Variant names:

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 0P and 18B. BP4_ModerateBP6_Very_StrongBA1

The NM_000203.5(IDUA):c.973-45G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.163 in 1,579,492 control chromosomes in the GnomAD database, including 22,633 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). The gene IDUA is included in the ClinGen Criteria Specification Registry.

Frequency

Genomes: 𝑓 0.17 ( 2418 hom., cov: 34)

Exomes 𝑓: 0.16 ( 20215 hom. )

Consequence

IDUA
NM_000203.5 intron

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:7

Conservation

PhyloP100: -1.97

Publications

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

IDUA links:

Genome browser will be placed here

ACMG classification

Specifications for IDUA are available in the ClinGen Criteria Specification Registry and recommended for reference when assigning criteria.

Classification was made for transcript

Our verdict: Benign. The variant received -18 ACMG points.

BP4

Computational evidence support a benign effect (REVEL=0.178).

BP6

Variant 4-1002224-G-C is Benign according to our data. Variant chr4-1002224-G-C is described in ClinVar as Benign. ClinVar VariationId is 255530.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.287 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000203.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
IDUA	NM_000203.5	MANE Select	c.973-45G>C	intron	N/A	NP_000194.2	P35475-1
IDUA	NM_001363576.1		c.577-45G>C	intron	N/A	NP_001350505.1
IDUA	NR_110313.1		n.1061-45G>C	intron	N/A

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
IDUA	ENST00000514224.2	TSL:2 MANE Select	c.973-45G>C	intron	N/A	ENSP00000425081.2	P35475-1
IDUA	ENST00000247933.9	TSL:1	c.973-45G>C	intron	N/A	ENSP00000247933.4	P35475-1
IDUA	ENST00000962389.1		c.1048-45G>C	intron	N/A	ENSP00000632448.1

Frequencies

GnomAD3 genomes

AF:

0.175

AC:

26508

AN:

151900

Hom.:

2422

Cov.:

show subpopulations

Gnomad AFR

AF:

0.220

Gnomad AMI

AF:

0.170

Gnomad AMR

AF:

0.124

Gnomad ASJ

AF:

0.165

Gnomad EAS

AF:

0.199

Gnomad SAS

AF:

0.301

Gnomad FIN

AF:

0.144

Gnomad MID

AF:

0.234

Gnomad NFE

AF:

0.152

Gnomad OTH

AF:

0.184

GnomAD2 exomes

AF:

0.177

AC:

33662

AN:

190542

AF XY:

0.186

show subpopulations

Gnomad AFR exome

AF:

0.229

Gnomad AMR exome

AF:

0.0818

Gnomad ASJ exome

AF:

0.162

Gnomad EAS exome

AF:

0.218

Gnomad FIN exome

AF:

0.146

Gnomad NFE exome

AF:

0.163

Gnomad OTH exome

AF:

0.176

GnomAD4 exome

AF:

0.162

AC:

230918

AN:

1427474

Hom.:

20215

Cov.:

AF XY:

0.166

AC XY:

117298

AN XY:

707398

show subpopulations

African (AFR)

AF:

0.229

AC:

7452

AN:

32544

American (AMR)

AF:

0.0873

AC:

3424

AN:

39242

Ashkenazi Jewish (ASJ)

AF:

0.161

AC:

4117

AN:

25558

East Asian (EAS)

AF:

0.170

AC:

6357

AN:

37374

South Asian (SAS)

AF:

0.299

AC:

24714

AN:

82758

European-Finnish (FIN)

AF:

0.152

AC:

7513

AN:

49400

Middle Eastern (MID)

AF:

0.203

AC:

1164

AN:

5734

European-Non Finnish (NFE)

AF:

0.152

AC:

166177

AN:

1095822

Other (OTH)

AF:

0.169

AC:

10000

AN:

59042

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.454

Heterozygous variant carriers

11617

23234

34851

46468

58085

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

6084

12168

18252

24336

30420

<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:

0.174

AC:

26507

AN:

152018

Hom.:

2418

Cov.:

AF XY:

0.174

AC XY:

12954

AN XY:

74336

show subpopulations

African (AFR)

AF:

0.220

AC:

9106

AN:

41454

American (AMR)

AF:

0.124

AC:

1898

AN:

15296

Ashkenazi Jewish (ASJ)

AF:

0.165

AC:

573

AN:

3468

East Asian (EAS)

AF:

0.199

AC:

1019

AN:

5130

South Asian (SAS)

AF:

0.300

AC:

1447

AN:

4820

European-Finnish (FIN)

AF:

0.144

AC:

1522

AN:

10586

Middle Eastern (MID)

AF:

0.228

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.152

AC:

10333

AN:

67948

Other (OTH)

AF:

0.183

AC:

387

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.493

Heterozygous variant carriers

1090

2181

3271

4362

5452

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

290

580

870

1160

1450

<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:

0.100

Hom.:

205

Bravo

AF:

0.172

Asia WGS

AF:

0.248

AC:

865

AN:

3476

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (2)

Hurler syndrome (1)

Mucopolysaccharidosis type 1 (1)

Mucopolysaccharidosis, MPS-I-H/S (1)

Mucopolysaccharidosis, MPS-I-S (1)

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.85

CADD

Benign

1.5

(source)

DANN

Uncertain

0.98

PhyloP100

-2.0

Mutation Taster

=100/0

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.050

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over