Genetic Variant IDUA:c.1190-11_1190-10dupCC (chr4-1002713-G-GCC) – ACMG Classification: Benign (-10 pts)

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP6_ModerateBS1BS2

The NM_000203.5(IDUA):c.1190-11_1190-10dupCC variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000409 in 1,363,574 control chromosomes in the GnomAD database, including 2 homozygotes. Variant has been reported in ClinVar as Benign (★).

Frequency

Genomes: 𝑓 0.0013 ( 2 hom., cov: 29)

Exomes 𝑓: 0.00030 ( 0 hom. )

Consequence

IDUA
NM_000203.5 intron

Scores

Not classified

Clinical Significance

Benign criteria provided, single submitter B:1

Conservation

PhyloP100: -0.792

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 was made for transcript

Our verdict: Benign. The variant received -10 ACMG points.

BP6

Variant 4-1002713-G-GCC is Benign according to our data. Variant chr4-1002713-G-GCC is described in ClinVar as [Benign]. Clinvar id is 1600766.Status of the report is criteria_provided_single_submitter, 1 stars.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00128 (192/149760) while in subpopulation AFR AF = 0.00373 (152/40706). AF 95% confidence interval is 0.00325. There are 2 homozygotes in GnomAd4. There are 90 alleles in the male GnomAd4 subpopulation. Median coverage is 29. This position FAILED quality control check.

BS2

High Homozygotes in GnomAd4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
IDUA	NM_000203.5 link	c.1190-11_1190-10dupCC		intron_variant	Intron 8 of 13	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.1190-19_1190-18insCC		intron_variant	Intron 8 of 13	2	NM_000203.5	ENSP00000425081.2		P35475-1

Frequencies

GnomAD3 genomes

AF:

0.00129

AC:

193

AN:

149662

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00374

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000396

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000595

Gnomad SAS

AF:

0.00106

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00654

Gnomad NFE

AF:

0.000342

Gnomad OTH

AF:

0.000978

GnomAD2 exomes

AF:

0.000738

AC:

AN:

73188

AF XY:

0.000916

show subpopulations

Gnomad AFR exome

AF:

0.00188

Gnomad AMR exome

AF:

0.000133

Gnomad ASJ exome

AF:

0.00105

Gnomad EAS exome

AF:

0.00192

Gnomad FIN exome

AF:

0.000233

Gnomad NFE exome

AF:

0.000452

Gnomad OTH exome

AF:

0.000908

GnomAD4 exome

AF:

0.000302

AC:

366

AN:

1213814

Hom.:

Cov.:

AF XY:

0.000333

AC XY:

200

AN XY:

601188

show subpopulations

Gnomad4 AFR exome

AF:

0.00112

AC:

AN:

24082

Gnomad4 AMR exome

AF:

0.000172

AC:

AN:

29050

Gnomad4 ASJ exome

AF:

0.000312

AC:

AN:

22404

Gnomad4 EAS exome

AF:

0.000173

AC:

AN:

28868

Gnomad4 SAS exome

AF:

0.00186

AC:

125

AN:

67350

Gnomad4 FIN exome

AF:

0.000122

AC:

AN:

32706

Gnomad4 NFE exome

AF:

0.000180

AC:

172

AN:

954808

Gnomad4 Remaining exome

AF:

0.000373

AC:

AN:

50936

⚠️ The allele balance in gnomAD4 Exomes is highly skewed (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Heterozygous variant carriers

103

138

172

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

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:

0.00128

AC:

192

AN:

149760

Hom.:

Cov.:

AF XY:

0.00123

AC XY:

AN XY:

73090

show subpopulations

Gnomad4 AFR

AF:

0.00373

AC:

0.00373409

AN:

0.00373409

Gnomad4 AMR

AF:

0.000396

AC:

0.000395831

AN:

0.000395831

Gnomad4 ASJ

AF:

0.00

AC:

AN:

Gnomad4 EAS

AF:

0.000596

AC:

0.000596421

AN:

0.000596421

Gnomad4 SAS

AF:

0.00106

AC:

0.00106022

AN:

0.00106022

Gnomad4 FIN

AF:

0.00

AC:

AN:

Gnomad4 NFE

AF:

0.000342

AC:

0.000342272

AN:

0.000342272

Gnomad4 OTH

AF:

0.000967

AC:

0.000967118

AN:

0.000967118

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Genome Het

Genome Hom

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:

0.000864

Hom.:

107

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Mucopolysaccharidosis type 1

Benign:1

Jan 06, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

Splicing

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.

4-1002713-GCCC-GCCCCC

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