dbSNP rs1340421020: IDUA:p.Glu404Lys (chr4-1002752-G-A) – 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.1210G>A(p.Glu404Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000015 in 1,332,194 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: not found (cov: 33)

Exomes 𝑓: 0.0000015 ( 0 hom. )

Consequence

IDUA
NM_000203.5 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.191

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;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein
IDUA	NM_000203.5 link	c.1210G>A	p.Glu404Lys	missense_variant	Exon 9 of 14	ENST00000514224.2	NP_000194.2
IDUA	NM_001363576.1 link	c.814G>A	p.Glu272Lys	missense_variant	Exon 8 of 13		NP_001350505.1
IDUA	XM_047415650.1 link	c.1210G>A	p.Glu404Lys	missense_variant	Exon 9 of 12		XP_047271606.1
IDUA	NR_110313.1 link	n.1298G>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.1210G>A	p.Glu404Lys	missense_variant	Exon 9 of 14	2	NM_000203.5	ENSP00000425081.2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000150

AC:

AN:

1332194

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

656752

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

26932

American (AMR)

AF:

0.00

AC:

AN:

30034

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

23594

East Asian (EAS)

AF:

0.00

AC:

AN:

29896

South Asian (SAS)

AF:

0.00

AC:

AN:

73456

European-Finnish (FIN)

AF:

0.00

AC:

AN:

33448

Middle Eastern (MID)

AF:

0.00

AC:

AN:

3930

European-Non Finnish (NFE)

AF:

9.47e-7

AC:

AN:

1055528

Other (OTH)

AF:

0.0000181

AC:

AN:

55376

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.450

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

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.14

BayesDel_addAF

Uncertain

0.037

BayesDel_noAF

Benign

-0.18

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.67

D;.

Eigen

Benign

0.055

Eigen_PC

Benign

-0.0018

FATHMM_MKL

Benign

0.65

LIST_S2

Benign

0.74

T;.

M_CAP

Pathogenic

0.92

MetaRNN

Uncertain

0.46

T;T

MetaSVM

Uncertain

0.52

MutationAssessor

Uncertain

2.6

M;.

PhyloP100

-0.19

PrimateAI

Pathogenic

0.81

PROVEAN

Benign

-2.0

N;N

REVEL

Uncertain

0.55

Sift

Benign

0.039

D;D

Sift4G

Benign

0.074

T;T

Polyphen

0.93

P;.

Vest4

0.15

MVP

0.98

MPC

0.58

ClinPred

0.91

GERP RS

3.0

Varity_R

0.30

gMVP

0.51

Mutation Taster

=83/17

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

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over