rs11934801

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2BP6

The NM_000203.5(IDUA):c.1225G>A(p.Gly409Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000752 in 1,330,556 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Benign in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G409E) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 7.5e-7 ( 0 hom. )

Consequence

IDUA
NM_000203.5 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:1

Conservation

PhyloP100: 0.768

Publications

16 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 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP6

Variant 4-1002767-G-A is Benign according to our data. Variant chr4-1002767-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 1084956.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
IDUA	NM_000203.5 link	c.1225G>A	p.Gly409Arg	missense_variant	Exon 9 of 14	ENST00000514224.2	NP_000194.2	P35475-1
IDUA	NM_001363576.1 link	c.829G>A	p.Gly277Arg	missense_variant	Exon 8 of 13		NP_001350505.1
IDUA	XM_047415650.1 link	c.1225G>A	p.Gly409Arg	missense_variant	Exon 9 of 12		XP_047271606.1
IDUA	NR_110313.1 link	n.1313G>A		non_coding_transcript_exon_variant	Exon 9 of 14

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
IDUA	ENST00000514224.2 link	c.1225G>A	p.Gly409Arg	missense_variant	Exon 9 of 14	2	NM_000203.5	ENSP00000425081.2		P35475-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

7.52e-7

AC:

AN:

1330556

Hom.:

Cov.:

AF XY:

0.00000152

AC XY:

AN XY:

655768

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

26864

American (AMR)

AF:

0.00

AC:

AN:

29492

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

23574

East Asian (EAS)

AF:

0.00

AC:

AN:

29684

South Asian (SAS)

AF:

0.00

AC:

AN:

73162

European-Finnish (FIN)

AF:

0.00

AC:

AN:

33404

Middle Eastern (MID)

AF:

0.00

AC:

AN:

3930

European-Non Finnish (NFE)

AF:

9.48e-7

AC:

AN:

1055108

Other (OTH)

AF:

0.00

AC:

AN:

55338

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000756

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:1

Apr 09, 2024

Mayo Clinic Laboratories, Mayo Clinic

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

PM2 -

Mucopolysaccharidosis type 1

Benign:1

Jan 11, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.18

BayesDel_addAF

Uncertain

0.12

BayesDel_noAF

Uncertain

-0.060

CADD

Benign

(source)

DANN

Benign

0.94

DEOGEN2

Pathogenic

0.83

D;.

Eigen

Benign

-0.10

Eigen_PC

Benign

-0.27

FATHMM_MKL

Benign

0.47

LIST_S2

Benign

0.72

T;.

M_CAP

Pathogenic

0.85

MetaRNN

Uncertain

0.43

T;T

MetaSVM

Uncertain

0.23

MutationAssessor

Benign

1.6

L;.

PhyloP100

0.77

PrimateAI

Pathogenic

0.82

PROVEAN

Uncertain

-2.8

D;D

REVEL

Uncertain

0.45

Sift

Benign

0.088

T;T

Sift4G

Benign

0.12

T;T

Polyphen

0.98

D;.

Vest4

0.24

MVP

0.99

MPC

0.32

ClinPred

0.40

GERP RS

2.7

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.26

gMVP

0.59

Mutation Taster

=88/12

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over