Genetic Variant IDUA:c.1190-18_1190-10dupCCCCCCCCC (chr4-1002713-G-GCCCCCCCCC) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_000203.5(IDUA):c.1190-18_1190-10dupCCCCCCCCC variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000823 in 1,214,898 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.0 ( 0 hom., cov: 29)

Exomes 𝑓: 8.2e-7 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

IDUA
NM_000203.5 intron

Scores

Not classified

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.792

Publications

0 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: Uncertain_significance. The variant received 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

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
IDUA	NM_000203.5	MANE Select	c.1190-18_1190-10dupCCCCCCCCC	intron	N/A	NP_000194.2
IDUA	NM_001363576.1		c.794-18_794-10dupCCCCCCCCC	intron	N/A	NP_001350505.1
IDUA	NR_110313.1		n.1278-18_1278-10dupCCCCCCCCC	intron	N/A

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein
IDUA	ENST00000514224.2	TSL:2 MANE Select	c.1190-18_1190-10dupCCCCCCCCC	intron	N/A	ENSP00000425081.2
IDUA	ENST00000247933.9	TSL:1	c.1190-18_1190-10dupCCCCCCCCC	intron	N/A	ENSP00000247933.4
IDUA	ENST00000514698.5	TSL:5	n.1297-18_1297-10dupCCCCCCCCC	intron	N/A

Frequencies

GnomAD3 genomes

AF:

0.00

AC:

AN:

149676

Hom.:

Cov.:

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

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

GnomAD4 exome

AF:

8.23e-7

AC:

AN:

1214898

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

601842

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

24134

American (AMR)

AF:

0.00

AC:

AN:

29060

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

22434

East Asian (EAS)

AF:

0.00

AC:

AN:

28878

South Asian (SAS)

AF:

0.00

AC:

AN:

67646

European-Finnish (FIN)

AF:

0.00

AC:

AN:

32742

Middle Eastern (MID)

AF:

0.00

AC:

AN:

3616

European-Non Finnish (NFE)

AF:

0.00000105

AC:

AN:

955414

Other (OTH)

AF:

0.00

AC:

AN:

50974

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.225

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

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

149676

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

72990

African (AFR)

AF:

0.00

AC:

AN:

40604

American (AMR)

AF:

0.00

AC:

AN:

15138

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3442

East Asian (EAS)

AF:

0.00

AC:

AN:

5044

South Asian (SAS)

AF:

0.00

AC:

AN:

4726

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10262

Middle Eastern (MID)

AF:

0.00

AC:

AN:

306

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

67210

Other (OTH)

AF:

0.00

AC:

AN:

2046

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

PhyloP100

-0.79

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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4-1002713-GCCCC-GCCCCCCCCCCCCC

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over