rs201826605

Positions:

• chr4-1001790-G-C

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_000203.5(IDUA):​c.701G>C​(p.Ser234Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000149 in 1,604,114 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00077 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000084 (0 hom.)
• Consequence: IDUA NM_000203.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:5 B:2
• Conservation: PhyloP100: 7.71

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]

ACMG classification

Verdict is Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.016695619).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
IDUA	NM_000203.5	c.701G>C	p.Ser234Thr	missense_variant	6/14	ENST00000514224.2	NP_000194.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
IDUA	ENST00000514224.2	c.701G>C	p.Ser234Thr	missense_variant	6/14	2	NM_000203.5	ENSP00000425081	P1

Frequencies

GnomAD3 genomes AF: 0.000742 AC: 113 AN: 152220 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00248

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000327

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00143

GnomAD3 exomes AF: 0.000201 AC: 46 AN: 229256 Hom.: 0 AF XY: 0.000119 AC XY: 15 AN XY: 126010

Gnomad AFR exome AF: 0.00258

Gnomad AMR exome AF: 0.000270

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: 0.00

Gnomad OTH exome AF: 0.000178

GnomAD4 exome AF: 0.0000840 AC: 122 AN: 1451776 Hom.: 0 Cov.: 34 AF XY: 0.0000679 AC XY: 49 AN XY: 722110

Gnomad4 AFR exome AF: 0.00248

Gnomad4 AMR exome AF: 0.000319

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000351

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000270

Gnomad4 OTH exome AF: 0.000250

GnomAD4 genome AF: 0.000768 AC: 117 AN: 152338 Hom.: 0 Cov.: 33 AF XY: 0.000779 AC XY: 58 AN XY: 74490

Gnomad4 AFR AF: 0.00255

Gnomad4 AMR AF: 0.000327

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00142

Alfa AF: 0.000271 Hom.: 0

Bravo AF: 0.000907

ESP6500AA AF: 0.00229 AC: 10

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000266 AC: 32

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:5 Benign:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Mucopolysaccharidosis type 1 Uncertain:2 Benign:1

Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 21, 2024	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Baylor Genetics	Aug 25, 2023	- -
Uncertain significance, no assertion criteria provided	clinical testing	Natera, Inc.	Jun 02, 2020	- -

not provided Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Jul 16, 2021	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Sep 26, 2023	- -

Mucopolysaccharidosis, MPS-I-S Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Baylor Genetics

Dec 03, 2020

This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868]. -

IDUA-related disorder Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Aug 03, 2024

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.24
BayesDel_addAF	Benign	-0.23	T
BayesDel_noAF	Benign	-0.10
CADD	Benign	22
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.57	D;.;D;D;.
Eigen	Benign	0.15
Eigen_PC	Uncertain	0.25
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Benign	0.79	T;T;.;.;.
M_CAP	Uncertain	0.19	D
MetaRNN	Benign	0.017	T;T;T;T;T
MetaSVM	Uncertain	-0.12	T
MutationAssessor	Benign	1.2	L;.;.;.;.
MutationTaster	Benign	1.0	N;N;N
PrimateAI	Uncertain	0.52	T
PROVEAN	Benign	-0.72	N;N;N;N;N
REVEL	Uncertain	0.37
Sift	Uncertain	0.019	D;D;T;T;D
Sift4G	Uncertain	0.037	D;D;D;T;D
Polyphen		0.53	P;.;.;.;.
Vest4		0.34
MVP		0.97
MPC		0.28
ClinPred		0.062	T
GERP RS		4.5
Varity_R		0.30
gMVP		0.80

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

Other links and lift over

dbSNP: rs201826605; hg19: chr4-995578;