rs73066479

Variant names:

• chr4-1002902-G-A
• rs73066479
• NM_000203.5:c.1360G>A

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BA1

This summary comes from the ClinGen Evidence Repository: The NM_000203.5:c.1360G>A variant in IDUA is a missense variant predicted to cause substitution of valine by isoleucine at amino acid 454 (p.Val454Ile). The highest population minor allele frequency in gnomAD v4.1.0 is 0.3004 (19925/66322 alleles; 3158 homozygotes; Grpmax Filtering AF 95% confidence = 0.2969) in the South Asian 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: 92630). 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/CA145872/MONDO:0001586/091

• Frequency:
  • Genomes: 𝑓 0.17 (2366 hom., cov: 33)
  • Exomes 𝑓: 0.16 (17534 hom.)
• Consequence: IDUA NM_000203.5 missense
• Clinical Significance: Benign reviewed by expert panel B:15
• Conservation: PhyloP100: 1.15
• Publications: 27 publications found

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: ClinGen, Myriad Women’s Health
• Scheie syndrome

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Genomics England PanelApp, G2P, Labcorp Genetics (formerly Invitae), Orphanet
• Hurler syndrome

  Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Orphanet, Genomics England PanelApp, PanelApp Australia
• Hurler-Scheie syndrome

  Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Genomics England PanelApp, Orphanet

ACMG classification

Our verdict: Benign. The variant received -8 ACMG points.

• BA1: For more information check the summary or visit ClinGen Evidence Repository.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IDUA	NM_000203.5	MANE Select	c.1360G>A	p.Val454Ile	missense	Exon 9 of 14	NP_000194.2
	IDUA	NM_001363576.1		c.964G>A	p.Val322Ile	missense	Exon 8 of 13	NP_001350505.1
	IDUA	NR_110313.1		n.1448G>A		non_coding_transcript_exon	Exon 9 of 14

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IDUA	ENST00000514224.2	TSL:2 MANE Select	c.1360G>A	p.Val454Ile	missense	Exon 9 of 14	ENSP00000425081.2
	IDUA	ENST00000247933.9	TSL:1	c.1360G>A	p.Val454Ile	missense	Exon 9 of 14	ENSP00000247933.4
	IDUA	ENST00000962389.1		c.1435G>A	p.Val479Ile	missense	Exon 10 of 15	ENSP00000632448.1

Frequencies

GnomAD3 genomes AF: 0.173 AC: 26206 AN: 151822 Hom.: 2370 Cov.: 33

Gnomad AFR AF: 0.213

Gnomad AMI AF: 0.171

Gnomad AMR AF: 0.124

Gnomad ASJ AF: 0.166

Gnomad EAS AF: 0.201

Gnomad SAS AF: 0.300

Gnomad FIN AF: 0.144

Gnomad MID AF: 0.236

Gnomad NFE AF: 0.152

Gnomad OTH AF: 0.183

GnomAD2 exomes AF: 0.203 AC: 7144 AN: 35220 AF XY: 0.219

Gnomad AFR exome AF: 0.247

Gnomad AMR exome AF: 0.0791

Gnomad ASJ exome AF: 0.195

Gnomad EAS exome AF: 0.255

Gnomad FIN exome AF: 0.169

Gnomad NFE exome AF: 0.183

Gnomad OTH exome AF: 0.203

GnomAD4 exome AF: 0.161 AC: 202361 AN: 1256844 Hom.: 17534 Cov.: 37 AF XY: 0.164 AC XY: 101139 AN XY: 615192

African (AFR) AF: 0.222 AC: 5512 AN: 24830

American (AMR) AF: 0.0948 AC: 1507 AN: 15894

Ashkenazi Jewish (ASJ) AF: 0.164 AC: 3211 AN: 19602

East Asian (EAS) AF: 0.158 AC: 4397 AN: 27792

South Asian (SAS) AF: 0.301 AC: 18483 AN: 61502

European-Finnish (FIN) AF: 0.159 AC: 4962 AN: 31246

Middle Eastern (MID) AF: 0.212 AC: 859 AN: 4044

European-Non Finnish (NFE) AF: 0.152 AC: 154678 AN: 1020122

Other (OTH) AF: 0.169 AC: 8752 AN: 51812

GnomAD4 genome AF: 0.172 AC: 26203 AN: 151930 Hom.: 2366 Cov.: 33 AF XY: 0.173 AC XY: 12841 AN XY: 74290

African (AFR) AF: 0.212 AC: 8807 AN: 41480

American (AMR) AF: 0.124 AC: 1890 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.166 AC: 575 AN: 3470

East Asian (EAS) AF: 0.201 AC: 1029 AN: 5118

South Asian (SAS) AF: 0.299 AC: 1442 AN: 4820

European-Finnish (FIN) AF: 0.144 AC: 1513 AN: 10540

Middle Eastern (MID) AF: 0.229 AC: 67 AN: 292

European-Non Finnish (NFE) AF: 0.152 AC: 10340 AN: 67902

Other (OTH) AF: 0.182 AC: 384 AN: 2110

Alfa AF: 0.154 Hom.: 298

Bravo AF: 0.170

TwinsUK AF: 0.166 AC: 614

ALSPAC AF: 0.159 AC: 614

ExAC AF: 0.114 AC: 3158

Asia WGS AF: 0.250 AC: 869 AN: 3462

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
-	-	4	Mucopolysaccharidosis type 1 (4)
-	-	4	not provided (4)
-	-	4	not specified (4)
-	-	1	Hurler syndrome (1)
-	-	1	Mucopolysaccharidosis, MPS-I-H/S (1)
-	-	1	Mucopolysaccharidosis, MPS-I-S (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.52	T
BayesDel_noAF	Benign	-0.38
CADD	Benign	3.8
DANN	Benign	0.47
DEOGEN2	Uncertain	0.47	T
Eigen	Benign	-1.0
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.039	N
LIST_S2	Benign	0.62	T
MetaRNN	Benign	0.0035	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.85	L
PhyloP100		1.1
PrimateAI	Uncertain	0.72	T
PROVEAN	Benign	-0.17	N
REVEL	Benign	0.094
Sift	Benign	0.81	T
Sift4G	Benign	0.41	T
Polyphen		0.0070	B
Vest4		0.016
MPC		0.16
ClinPred		0.0022	T
GERP RS		0.14
Varity_R		0.13
gMVP		0.15
Mutation Taster		=95/5	polymorphism (auto)

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

Other links and lift over

dbSNP: rs73066479; hg19: chr4-996690; COSMIC: COSV107213736; COSMIC: COSV107213736;