4-1002411-A-G

Variant names:

Variant summary

Our verdict is Likely pathogenic. The variant received 7 ACMG points: 7P and 0B. PM1PM2PP3PP5_Moderate

The NM_000203.5(IDUA):c.1115A>G(p.Asn372Ser) variant causes a missense change. The variant allele was found at a frequency of 0.000000698 in 1,432,042 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★).

Frequency

Genomes: not found (cov: 34)

Exomes 𝑓: 7.0e-7 ( 0 hom. )

Consequence

IDUA
NM_000203.5 missense

Scores

Clinical Significance

Likely pathogenic criteria provided, single submitter P:1U:1

Conservation

PhyloP100: 5.08

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: Likely_pathogenic. The variant received 7 ACMG points.

PM1

In a hotspot region, there are 5 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 22 uncertain in NM_000203.5

PM2

Very rare variant in population databases, with high coverage;

PP3

Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.

PP5

Variant 4-1002411-A-G is Pathogenic according to our data. Variant chr4-1002411-A-G is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 554765.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
IDUA	NM_000203.5 link	c.1115A>G	p.Asn372Ser	missense_variant	Exon 8 of 14	ENST00000514224.2	NP_000194.2	P35475-1
IDUA	NM_001363576.1 link	c.719A>G	p.Asn240Ser	missense_variant	Exon 7 of 13		NP_001350505.1
IDUA	XM_047415650.1 link	c.1115A>G	p.Asn372Ser	missense_variant	Exon 8 of 12		XP_047271606.1
IDUA	NR_110313.1 link	n.1203A>G		non_coding_transcript_exon_variant	Exon 8 of 14

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
IDUA	ENST00000514224.2 link	c.1115A>G	p.Asn372Ser	missense_variant	Exon 8 of 14	2	NM_000203.5	ENSP00000425081.2	P35475-1
IDUA	ENST00000247933.9 link	c.1115A>G	p.Asn372Ser	missense_variant	Exon 8 of 14	1		ENSP00000247933.4	P35475-1
IDUA	ENST00000514698.5 link	n.1222A>G		non_coding_transcript_exon_variant	Exon 5 of 11	5
IDUA	ENST00000652070.1 link	n.1171A>G		non_coding_transcript_exon_variant	Exon 7 of 13

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.98e-7

AC:

AN:

1432042

Hom.:

Cov.:

AF XY:

0.00000141

AC XY:

AN XY:

710182

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

32510

American (AMR)

AF:

0.00

AC:

AN:

39744

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25590

East Asian (EAS)

AF:

0.00

AC:

AN:

37540

South Asian (SAS)

AF:

0.00

AC:

AN:

83304

European-Finnish (FIN)

AF:

0.00

AC:

AN:

49592

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5742

European-Non Finnish (NFE)

AF:

9.10e-7

AC:

AN:

1098730

Other (OTH)

AF:

0.00

AC:

AN:

59290

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.575

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Mucopolysaccharidosis type 1

Pathogenic:1

Jul 23, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces asparagine, which is neutral and polar, with serine, which is neutral and polar, at codon 372 of the IDUA protein (p.Asn372Ser). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with mucopolysaccharidosis type I (PMID: 27146977). ClinVar contains an entry for this variant (Variation ID: 554765). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on IDUA protein function. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. -

Hurler syndrome

Uncertain:1

Nov 02, 2017

Counsyl

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:clinical testing

This submission and the accompanying classification are no longer maintained by the submitter. For more information on current observations and classification, please contact variantquestions@myriad.com. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.32

BayesDel_addAF

Uncertain

0.094

BayesDel_noAF

Benign

-0.10

CADD

Pathogenic

(source)

DANN

Uncertain

0.99

DEOGEN2

Pathogenic

0.94

D;.

Eigen

Uncertain

0.30

Eigen_PC

Uncertain

0.24

FATHMM_MKL

Uncertain

0.93

LIST_S2

Uncertain

0.95

D;.

M_CAP

Pathogenic

0.76

MetaRNN

Pathogenic

0.92

D;D

MetaSVM

Pathogenic

0.86

MutationAssessor

Benign

2.0

M;.

PhyloP100

5.1

PrimateAI

Uncertain

0.75

PROVEAN

Pathogenic

-4.5

D;D

REVEL

Pathogenic

0.69

Sift

Uncertain

0.0070

D;D

Sift4G

Uncertain

0.047

D;T

Polyphen

0.93

P;.

Vest4

0.88

MVP

0.97

MPC

0.38

ClinPred

0.98

GERP RS

4.1

Varity_R

0.60

gMVP

0.76

Mutation Taster

=6/94

disease causing

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.74

Details are displayed if max score is > 0.2

DS_DG_spliceai

0.74

Position offset: -5

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

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

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