dbSNP rs3755956: IDUA:c.300-44C>T (chr4-1000568-C-T) – ACMG Classification: Benign (-20 pts)

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_000203.5(IDUA):c.300-44C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0379 in 1,451,130 control chromosomes in the GnomAD database, including 1,345 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 0.032 ( 125 hom., cov: 34)

Exomes 𝑓: 0.039 ( 1220 hom. )

Consequence

IDUA
NM_000203.5 intron

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: -1.77

Publications

3 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 -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.87).

BP6

Variant 4-1000568-C-T is Benign according to our data. Variant chr4-1000568-C-T is described in ClinVar as Benign. ClinVar VariationId is 255526.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.111 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.300-44C>T	intron	N/A	NP_000194.2	P35475-1
IDUA	NM_001363576.1		c.-97-44C>T	intron	N/A	NP_001350505.1
IDUA	NR_110313.1		n.388-44C>T	intron	N/A

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
IDUA	ENST00000514224.2	TSL:2 MANE Select	c.300-44C>T	intron	N/A	ENSP00000425081.2	P35475-1
IDUA	ENST00000247933.9	TSL:1	c.300-44C>T	intron	N/A	ENSP00000247933.4	P35475-1
IDUA	ENST00000962389.1		c.375-44C>T	intron	N/A	ENSP00000632448.1

Frequencies

GnomAD3 genomes

AF:

0.0323

AC:

4915

AN:

152238

Hom.:

124

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0110

Gnomad AMI

AF:

0.00329

Gnomad AMR

AF:

0.0327

Gnomad ASJ

AF:

0.0161

Gnomad EAS

AF:

0.119

Gnomad SAS

AF:

0.0170

Gnomad FIN

AF:

0.0490

Gnomad MID

AF:

0.0316

Gnomad NFE

AF:

0.0377

Gnomad OTH

AF:

0.0507

GnomAD2 exomes

AF:

0.0372

AC:

9248

AN:

248650

AF XY:

0.0361

show subpopulations

Gnomad AFR exome

AF:

0.00949

Gnomad AMR exome

AF:

0.0199

Gnomad ASJ exome

AF:

0.0155

Gnomad EAS exome

AF:

0.119

Gnomad FIN exome

AF:

0.0516

Gnomad NFE exome

AF:

0.0385

Gnomad OTH exome

AF:

0.0385

GnomAD4 exome

AF:

0.0385

AC:

50030

AN:

1298774

Hom.:

1220

Cov.:

AF XY:

0.0376

AC XY:

24643

AN XY:

654688

show subpopulations

African (AFR)

AF:

0.00954

AC:

290

AN:

30390

American (AMR)

AF:

0.0209

AC:

930

AN:

44516

Ashkenazi Jewish (ASJ)

AF:

0.0137

AC:

345

AN:

25154

East Asian (EAS)

AF:

0.114

AC:

4442

AN:

38926

South Asian (SAS)

AF:

0.0137

AC:

1133

AN:

82886

European-Finnish (FIN)

AF:

0.0531

AC:

2765

AN:

52034

Middle Eastern (MID)

AF:

0.0259

AC:

141

AN:

5450

European-Non Finnish (NFE)

AF:

0.0392

AC:

37758

AN:

964318

Other (OTH)

AF:

0.0404

AC:

2226

AN:

55100

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.514

Heterozygous variant carriers

2672

5344

8015

10687

13359

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

1378

2756

4134

5512

6890

<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:

0.0323

AC:

4919

AN:

152356

Hom.:

125

Cov.:

AF XY:

0.0327

AC XY:

2433

AN XY:

74508

show subpopulations

African (AFR)

AF:

0.0109

AC:

454

AN:

41580

American (AMR)

AF:

0.0327

AC:

500

AN:

15310

Ashkenazi Jewish (ASJ)

AF:

0.0161

AC:

AN:

3470

East Asian (EAS)

AF:

0.119

AC:

617

AN:

5188

South Asian (SAS)

AF:

0.0170

AC:

AN:

4832

European-Finnish (FIN)

AF:

0.0490

AC:

520

AN:

10620

Middle Eastern (MID)

AF:

0.0340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0377

AC:

2562

AN:

68036

Other (OTH)

AF:

0.0544

AC:

115

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.497

Heterozygous variant carriers

264

529

793

1058

1322

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

116

174

232

290

<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:

0.0313

Hom.:

Bravo

AF:

0.0315

Asia WGS

AF:

0.0730

AC:

254

AN:

3478

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (2)

Mucopolysaccharidosis type 1 (1)

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.87

CADD

Benign

0.42

(source)

DANN

Benign

0.53

PhyloP100

-1.8

Mutation Taster

=100/0

polymorphism (auto)

(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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over