dbSNP rs76722191: IDUA:p.Val322Glu (chr4-1002154-T-A) – ACMG Classification: Benign (-15 pts)

Variant summary

Our verdict is Benign. The variant received -15 ACMG points: 3P and 18B. PM1PP3BP4_ModerateBP6_Very_StrongBS1BS2

The NM_000203.5(IDUA):c.965T>A(p.Val322Glu) variant causes a missense change. The variant allele was found at a frequency of 0.000506 in 1,556,798 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign,other (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V322L) has been classified as Uncertain significance. The gene IDUA is included in the ClinGen Criteria Specification Registry.

Frequency

Genomes: 𝑓 0.0025 ( 0 hom., cov: 34)

Exomes 𝑓: 0.00029 ( 2 hom. )

Consequence

IDUA
NM_000203.5 missense

Scores

Clinical Significance

Benign/Likely benign; other criteria provided, multiple submitters, no conflicts B:4O:2

Conservation

PhyloP100: 4.78

Publications

18 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: Myriad Women’s Health, ClinGen
Scheie syndrome
Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, Genomics England PanelApp, Labcorp Genetics (formerly Invitae), G2P
Hurler syndrome
Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Orphanet, Genomics England PanelApp
Hurler-Scheie syndrome
Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Genomics England PanelApp, Orphanet

IDUA links:

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ACMG classification

Specifications for IDUA are available in the ClinGen Criteria Specification Registry and recommended for reference when assigning criteria.

Classification was made for transcript

Our verdict: Benign. The variant received -15 ACMG points.

PM1

In a hotspot region, there are 5 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 10 uncertain in NM_000203.5

PP3

Multiple lines of computational evidence support a deleterious effect 9: AlphaMissense, BayesDel_addAF, BayesDel_noAF, Cadd, M_CAP, PrimateAI, PROVEAN, REVEL, REVEL [when max_spliceai, FATHMM_MKL, MetaRNN, MutationTaster was below the threshold]

BP4

Computational evidence support a benign effect (MetaRNN=0.073826075).

BP6

Variant 4-1002154-T-A is Benign according to our data. Variant chr4-1002154-T-A is described in ClinVar as Benign/Likely_benign|other. ClinVar VariationId is 222992.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00249 (379/152160) while in subpopulation AFR AF = 0.00845 (351/41518). AF 95% confidence interval is 0.00772. There are 0 homozygotes in GnomAd4. There are 182 alleles in the male GnomAd4 subpopulation. Median coverage is 34. This position passed quality control check.

BS2

High Homozygotes in GnomAdExome4 at 2 AR gene

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	HGVSp	Effect	Exon Rank	Protein	UniProt
IDUA	NM_000203.5	MANE Select	c.965T>A	p.Val322Glu	missense	Exon 7 of 14	NP_000194.2	P35475-1
IDUA	NM_001363576.1		c.569T>A	p.Val190Glu	missense	Exon 6 of 13	NP_001350505.1
IDUA	NR_110313.1		n.1053T>A		non_coding_transcript_exon	Exon 7 of 14

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
IDUA	ENST00000514224.2	TSL:2 MANE Select	c.965T>A	p.Val322Glu	missense	Exon 7 of 14	ENSP00000425081.2	P35475-1
IDUA	ENST00000247933.9	TSL:1	c.965T>A	p.Val322Glu	missense	Exon 7 of 14	ENSP00000247933.4	P35475-1
IDUA	ENST00000962389.1		c.1040T>A	p.Val347Glu	missense	Exon 8 of 15	ENSP00000632448.1

Frequencies

GnomAD3 genomes

AF:

0.00248

AC:

377

AN:

152042

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00843

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00118

Gnomad ASJ

AF:

0.00115

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000294

Gnomad OTH

AF:

0.00191

GnomAD2 exomes

AF:

0.000631

AC:

101

AN:

159948

AF XY:

0.000457

show subpopulations

Gnomad AFR exome

AF:

0.00884

Gnomad AMR exome

AF:

0.000437

Gnomad ASJ exome

AF:

0.000953

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000320

Gnomad OTH exome

AF:

0.000225

GnomAD4 exome

AF:

0.000291

AC:

409

AN:

1404638

Hom.:

Cov.:

AF XY:

0.000261

AC XY:

181

AN XY:

693102

show subpopulations

African (AFR)

AF:

0.00926

AC:

297

AN:

32068

American (AMR)

AF:

0.000413

AC:

AN:

36296

Ashkenazi Jewish (ASJ)

AF:

0.00115

AC:

AN:

25110

East Asian (EAS)

AF:

0.00

AC:

AN:

36466

South Asian (SAS)

AF:

0.0000250

AC:

AN:

79914

European-Finnish (FIN)

AF:

0.00

AC:

AN:

48302

Middle Eastern (MID)

AF:

0.000880

AC:

AN:

5684

European-Non Finnish (NFE)

AF:

0.0000102

AC:

AN:

1082636

Other (OTH)

AF:

0.000860

AC:

AN:

58162

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.466

Heterozygous variant carriers

116

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome 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

GnomAD4 genome

AF:

0.00249

AC:

379

AN:

152160

Hom.:

Cov.:

AF XY:

0.00245

AC XY:

182

AN XY:

74384

show subpopulations

African (AFR)

AF:

0.00845

AC:

351

AN:

41518

American (AMR)

AF:

0.00118

AC:

AN:

15298

Ashkenazi Jewish (ASJ)

AF:

0.00115

AC:

AN:

3466

East Asian (EAS)

AF:

0.00

AC:

AN:

5142

South Asian (SAS)

AF:

0.00

AC:

AN:

4816

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10618

Middle Eastern (MID)

AF:

0.00

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.0000294

AC:

AN:

67986

Other (OTH)

AF:

0.00189

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome 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

Alfa

AF:

0.000761

Hom.:

Bravo

AF:

0.00251

ESP6500AA

AF:

0.00640

AC:

ESP6500EA

AF:

0.000120

AC:

ExAC

AF:

0.000491

AC:

Asia WGS

AF:

0.00115

AC:

AN:

3478

ClinVar

ClinVar submissions

Significance:Benign/Likely benign; other

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Hurler syndrome (1)

Inborn genetic diseases (1)

Mucopolysaccharidosis type 1 (3)

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.87

BayesDel_addAF

Pathogenic

0.17

BayesDel_noAF

Pathogenic

0.48

CADD

Pathogenic

(source)

DANN

Uncertain

0.99

DEOGEN2

Pathogenic

0.96

Eigen

Uncertain

0.68

Eigen_PC

Uncertain

0.60

FATHMM_MKL

Uncertain

0.94

LIST_S2

Uncertain

0.90

M_CAP

Pathogenic

0.69

MetaRNN

Benign

0.074

MetaSVM

Pathogenic

0.88

MutationAssessor

Uncertain

2.6

PhyloP100

4.8

PrimateAI

Pathogenic

0.81

PROVEAN

Pathogenic

-5.5

REVEL

Pathogenic

0.96

Sift

Uncertain

0.0010

Sift4G

Uncertain

0.0020

Polyphen

1.0

Vest4

0.94

MVP

1.0

MPC

0.97

ClinPred

0.068

GERP RS

5.2

Varity_R

0.93

gMVP

0.97

Mutation Taster

=13/87

disease causing

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.12

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over