rs10794537

chr4-987183-T-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000203.5(IDUA):c.99T>G(p.His33Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.815 in 1,472,526 control chromosomes in the GnomAD database, including 490,912 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Benignin ClinVar.

• Frequency:
  • Genomes: 𝑓 0.85 (55748 hom., cov: 38)
  • Exomes 𝑓: 0.81 (435164 hom.)
• Consequence: IDUA NM_000203.5 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:14
• Conservation: PhyloP100: -2.44

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]

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]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=7.3228284E-7).
• BP6: Variant 4-987183-T-G is Benign according to our data. Variant chr4-987183-T-G is described in ClinVar as [Benign]. Clinvar id is 92651.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr4-987183-T-G is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.95 is higher than 0.05.

Transcripts

RefSeq

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

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
IDUA	ENST00000514224.2	c.99T>G	p.His33Gln	missense_variant	1/14	2	NM_000203.5	P1

Frequencies

GnomAD3 genomes AF: 0.853 AC: 129624 AN: 152032 Hom.: 55703 Cov.: 38

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

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.: 42 AF XY: 0.815 AC XY: 530301 AN XY: 650812

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.: 38 AF XY: 0.854 AC XY: 63531 AN XY: 74384

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:14

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:6

Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Aug 25, 2017	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
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 “With Benign Allele”, 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, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
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	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. -
Benign, no assertion criteria provided	clinical testing	Natera, Inc.	May 11, 2017	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -

not provided Benign:2

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	T
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	N
LIST_S2	Benign	0.041	T;T
MetaRNN	Benign	7.3e-7	T;T
MetaSVM	Benign	-0.97	T
MutationAssessor	Benign	-0.69	N;.
MutationTaster	Benign	1.0	P;P;P
PrimateAI	Pathogenic	0.81	D
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	T
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

Other links and lift over

dbSNP: rs10794537; hg19: chr4-980971; COSMIC: COSV56101815; COSMIC: COSV56101815;