rs10794537

Positions:

chr4-987183-T-G

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BA1

This summary comes from the ClinGen Evidence Repository: The NM_000203.5:c.99T>G variant in IDUA is a missense variant predicted to cause substitution of histidine by glutamine at amino acid 33 (p.His33Gln). The highest population minor allele frequency in gnomAD v4.1.0 is 0.9605 (65474/68164 alleles; 31451 homozygotes; Grpmax Filtering AF 95% confidence = 0.9544) in the African/African American population, which is higher than the ClinGen Lysosomal Diseases VCEP’s threshold for BA1 (>0.005), and therefore meets this criterion (BA1). There is a ClinVar entry for this variant (Variation ID: 92651). In summary, this variant meets the criteria to be classified as benign for mucopolysaccharidosis type 1. IDUA-specific ACMG/AMP criteria applied, as specified by the ClinGen Lysosomal Diseases Variant Curation Expert Panel (Specifications Version 1.0.0): BA1.(Classification approved by the ClinGen Lysosomal Diseases Variant Curation Expert Panel on December 6, 2024) LINK:https://erepo.genome.network/evrepo/ui/classification/CA145894/MONDO:0001586/091

Frequency

Genomes: 𝑓 0.85 ( 55748 hom., cov: 38)

Exomes 𝑓: 0.81 ( 435164 hom. )

Consequence

IDUA
NM_000203.5 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:15

Conservation

PhyloP100: -2.44

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:

SLC26A1 (HGNC:10993): (solute carrier family 26 member 1) This gene is a member of a family of sulfate/anion transporter genes. Family members are well conserved in their genomic (number and size of exons) and protein (aa length among species) structures, but have markedly different tissue expression patterns. This gene is primarily expressed in the liver, pancreas, and brain. Three splice variants that encode different isoforms have been identified. [provided by RefSeq, Jul 2008]

SLC26A1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -8 ACMG points.

BA1

For more information check the summary or visit ClinGen Evidence Repository.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
IDUA	NM_000203.5 linkuse as main transcript	c.99T>G	p.His33Gln	missense_variant	1/14	ENST00000514224.2	NP_000194.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
IDUA	ENST00000514224.2 linkuse as main transcript	c.99T>G	p.His33Gln	missense_variant	1/14	2	NM_000203.5	ENSP00000425081	P1	P35475-1

Frequencies

GnomAD3 genomes

AF:

0.853

AC:

129624

AN:

152032

Hom.:

55703

Cov.:

show subpopulations

Gnomad AFR

AF:

0.958

Gnomad AMI

AF:

0.685

Gnomad AMR

AF:

0.820

Gnomad ASJ

AF:

0.891

Gnomad EAS

AF:

0.853

Gnomad SAS

AF:

0.935

Gnomad FIN

AF:

0.789

Gnomad MID

AF:

0.939

Gnomad NFE

AF:

0.800

Gnomad OTH

AF:

0.860

GnomAD3 exomes

AF:

0.839

AC:

67457

AN:

80392

Hom.:

28504

AF XY:

0.849

AC XY:

39097

AN XY:

46066

show subpopulations

Gnomad AFR exome

AF:

0.962

Gnomad AMR exome

AF:

0.797

Gnomad ASJ exome

AF:

0.895

Gnomad EAS exome

AF:

0.855

Gnomad SAS exome

AF:

0.928

Gnomad FIN exome

AF:

0.787

Gnomad NFE exome

AF:

0.803

Gnomad OTH exome

AF:

0.834

GnomAD4 exome

AF:

0.810

AC:

1070032

AN:

1320386

Hom.:

435164

Cov.:

AF XY:

0.815

AC XY:

530301

AN XY:

650812

show subpopulations

Gnomad4 AFR exome

AF:

0.965

Gnomad4 AMR exome

AF:

0.801

Gnomad4 ASJ exome

AF:

0.895

Gnomad4 EAS exome

AF:

0.857

Gnomad4 SAS exome

AF:

0.928

Gnomad4 FIN exome

AF:

0.790

Gnomad4 NFE exome

AF:

0.794

Gnomad4 OTH exome

AF:

0.835

GnomAD4 genome

AF:

0.853

AC:

129714

AN:

152140

Hom.:

55748

Cov.:

AF XY:

0.854

AC XY:

63531

AN XY:

74384

show subpopulations

Gnomad4 AFR

AF:

0.958

Gnomad4 AMR

AF:

0.819

Gnomad4 ASJ

AF:

0.891

Gnomad4 EAS

AF:

0.853

Gnomad4 SAS

AF:

0.935

Gnomad4 FIN

AF:

0.789

Gnomad4 NFE

AF:

0.800

Gnomad4 OTH

AF:

0.861

Alfa

AF:

0.816

Hom.:

6355

Bravo

AF:

0.858

TwinsUK

AF:

0.786

AC:

2916

ALSPAC

AF:

0.797

AC:

3073

ExAC

AF:

0.853

AC:

10917

Asia WGS

AF:

0.916

AC:

3163

AN:

3452

ClinVar

Significance: Benign

Submissions summary: Benign:15

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:6

Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Aug 25, 2017	- -
Benign, no assertion criteria provided	clinical testing	Department of Pathology and Laboratory Medicine, Sinai Health System	-	The IDUA p.His33Gln variant was identified in the literature as polymorphism/benign in studies of patients with Mucopolysaccharidosis type I (MPS I) disease (Chkioua_2011_21639919, Azab_2017_28649516, Atceken_2016_27511503, Lin_2013_24053568, Li_2002_12509712). The variant was also identified in the following databases: dbSNP (ID: rs10794537) as â€šÃ„ÃºWith Benign Alleleâ€šÃ„Ã¹, ClinVar (3x, as benign), Clinvitae database (3x as benign). This variant was identified in the 1000 Genomes Project in 4467 of 5008 chromosomes (frequency: 0.9), the genome Aggregation Database (beta, October 19th 2016) in 9303 (4255 homozygous) of 10182 chromosomes (freq. 0.9), the Exome Aggregation Consortium database (August 8th 2016) in 92436 (39108 homozygous) of 110100 chromosomes (freq. 0.83) in the following populations: African in 9151 of 9570 chromosomes (freq. 0.95), other in 2692 of 3248 chromosomes (freq. 0.82), Latino in 13176 of 16524 chromosomes (freq. 0.8), European non Finnish in 35257 of 44264 chromosomes (freq. 0.8), Ashkenazi Jewish in 6104 of 6814 chromosomes (freq. 0.9), east Asian in 3947 of 4612 chromosomes (freq. 0.85), Finnish in 6417 of 8150 chromosomes (freq. 0.8), and South Asian in 15692 of 16918 chromosomes (freq. 0.8), increasing the likelihood this is a high frequency benign variant, seen in all populations. The p.His33 residue is not conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; however, this information is not predictive enough to rule out pathogenicity. The variant occurs outside of the splicing consensus sequence and 4 of 5 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) predict a greater than 10% difference in splicing. However, this information is not predictive enough to assume pathogenicity. In summary, based on the above information, this variant meets our laboratory's criteria to be classified as benign. -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -

Mucopolysaccharidosis type 1

Benign:3

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Benign, no assertion criteria provided	clinical testing	Natera, Inc.	May 11, 2017	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

not provided

Benign:3

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, no assertion criteria provided	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Oct 23, 2015	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Apr 03, 2018	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Mucopolysaccharidosis, MPS-I-H/S

Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 14, 2021

- -

Mucopolysaccharidosis, MPS-I-S

Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 14, 2021

- -

Hurler syndrome

Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 14, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.098

BayesDel_addAF

Benign

-0.48

BayesDel_noAF

Benign

-0.32

CADD

Benign

0.34

DANN

Benign

0.67

DEOGEN2

Uncertain

0.45

T;.

Eigen

Benign

-1.6

Eigen_PC

Benign

-1.5

FATHMM_MKL

Benign

0.059

LIST_S2

Benign

0.041

T;T

MetaRNN

Benign

7.3e-7

T;T

MetaSVM

Benign

-0.97

MutationAssessor

Benign

-0.69

N;.

MutationTaster

Benign

1.0

P;P;P

PrimateAI

Pathogenic

0.81

PROVEAN

Benign

0.75

N;N

REVEL

Uncertain

0.39

Sift

Benign

0.46

T;T

Sift4G

Benign

0.66

T;T

Polyphen

0.0

B;.

Vest4

0.011

MutPred

0.40

Gain of MoRF binding (P = 0.1031);Gain of MoRF binding (P = 0.1031);

MPC

0.19

ClinPred

0.0017

GERP RS

-0.90

Varity_R

0.10

gMVP

0.40

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

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