rs183347428

Positions:

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 2P and 20B. PM1BP4_StrongBP6_Very_StrongBS1BS2

The NM_000203.5(IDUA):c.667G>A(p.Asp223Asn) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000331 in 1,598,148 control chromosomes in the GnomAD database, including 3 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. D223Y) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0020 ( 3 hom., cov: 34)

Exomes 𝑓: 0.00016 ( 0 hom. )

Consequence

IDUA
NM_000203.5 missense

Scores

Clinical Significance

Benign/Likely benign; other criteria provided, multiple submitters, no conflicts U:1B:3O:2

Conservation

PhyloP100: 9.68

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -18 ACMG points.

PM1

In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 6 uncertain in NM_000203.5

BP4

Computational evidence support a benign effect (MetaRNN=0.020062923).

BP6

Variant 4-1001756-G-A is Benign according to our data. Variant chr4-1001756-G-A is described in ClinVar as [Likely_benign, other]. Clinvar id is 426817.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 = 0.00199 (303/152122) while in subpopulation AFR AF= 0.00696 (289/41508). AF 95% confidence interval is 0.0063. There are 3 homozygotes in gnomad4. There are 152 alleles in male gnomad4 subpopulation. Median coverage is 34. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 3 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
IDUA	NM_000203.5 linkuse as main transcript	c.667G>A	p.Asp223Asn	missense_variant	6/14	ENST00000514224.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
IDUA	ENST00000514224.2 linkuse as main transcript	c.667G>A	p.Asp223Asn	missense_variant	6/14	2	NM_000203.5	P1	P35475-1

Frequencies

GnomAD3 genomes

AF:

0.00199

AC:

303

AN:

152004

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00698

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000916

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

GnomAD3 exomes

AF:

0.000363

AC:

AN:

220268

Hom.:

AF XY:

0.000238

AC XY:

AN XY:

121962

show subpopulations

Gnomad AFR exome

AF:

0.00557

Gnomad AMR exome

AF:

0.000181

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000100

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000156

AC:

226

AN:

1446026

Hom.:

Cov.:

AF XY:

0.000145

AC XY:

104

AN XY:

719450

show subpopulations

Gnomad4 AFR exome

AF:

0.00573

Gnomad4 AMR exome

AF:

0.000250

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000270

Gnomad4 OTH exome

AF:

0.000350

GnomAD4 genome

AF:

0.00199

AC:

303

AN:

152122

Hom.:

Cov.:

AF XY:

0.00204

AC XY:

152

AN XY:

74366

show subpopulations

Gnomad4 AFR

AF:

0.00696

Gnomad4 AMR

AF:

0.000915

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000117

Hom.:

Bravo

AF:

0.00201

ESP6500AA

AF:

0.00529

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.000442

AC:

ClinVar

Significance: Benign/Likely benign; other

Submissions summary: Uncertain:1Benign:3Other:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Mucopolysaccharidosis type 1

Benign:1Other:2

Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Apr 23, 2020	- -
not provided, no classification provided	literature only	GeneReviews	-	Pseudodeficiency variants -
other, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 19, 2018	- pseudodeficiency allele

not provided

Uncertain:1Benign:1

Uncertain significance, no assertion criteria provided	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	May 16, 2017	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Sep 28, 2018	This variant is associated with the following publications: (PMID: 27939258, 27238910) -

Inborn genetic diseases

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 19, 2021

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.64

BayesDel_addAF

Benign

-0.17

BayesDel_noAF

Uncertain

-0.020

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.79

D;.;D;D;.

Eigen

Pathogenic

0.68

Eigen_PC

Uncertain

0.61

FATHMM_MKL

Uncertain

0.96

LIST_S2

Uncertain

0.96

D;D;.;.;.

M_CAP

Pathogenic

0.54

MetaRNN

Benign

0.020

T;T;T;T;T

MetaSVM

Uncertain

0.75

MutationAssessor

Uncertain

2.6

M;.;.;.;.

MutationTaster

Benign

1.0

D;D;D

PrimateAI

Uncertain

0.58

PROVEAN

Uncertain

-3.0

D;D;D;D;D

REVEL

Pathogenic

0.71

Sift

Benign

0.26

T;T;T;T;T

Sift4G

Benign

0.12

T;T;T;T;T

Polyphen

1.0

D;.;.;.;.

Vest4

0.77

MVP

0.99

MPC

0.73

ClinPred

0.098

GERP RS

5.4

Varity_R

0.73

gMVP

0.92

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over