chr4-1000664-C-T

Variant names:

• chr4-1000664-C-T
• rs3755954
• NM_000203.5:c.352C>T

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.352C>T variant in IDUA is a synonymous (silent) variant (p.Leu118=). The highest population minor allele frequency in gnomAD v4.1.0 is 0.2517 (296774/1178988 alleles; 37458 homozygotes) in the European non-Finnish 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: 92642). 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/CA145883/MONDO:0001586/091

• Frequency:
  • Genomes: 𝑓 0.22 (3827 hom., cov: 34)
  • Exomes 𝑓: 0.23 (40947 hom.)
• Consequence: IDUA ENST00000514224.2 synonymous
• Clinical Significance: Benign reviewed by expert panel B:16
• Conservation: PhyloP100: -0.107
• Publications: 19 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: ENST00000514224.2. 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.352C>T	p.Leu118Leu	synonymous	Exon 3 of 14	NP_000194.2
	IDUA	NM_001363576.1		c.-45C>T		5_prime_UTR_premature_start_codon_gain	Exon 2 of 13	NP_001350505.1
	IDUA	NR_110313.1		n.440C>T		non_coding_transcript_exon	Exon 3 of 14

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IDUA	ENST00000514224.2	TSL:2 MANE Select	c.352C>T	p.Leu118Leu	synonymous	Exon 3 of 14	ENSP00000425081.2
	IDUA	ENST00000247933.9	TSL:1	c.352C>T	p.Leu118Leu	synonymous	Exon 3 of 14	ENSP00000247933.4
	IDUA	ENST00000502910.5	TSL:3	c.211C>T	p.Leu71Leu	synonymous	Exon 2 of 6	ENSP00000422952.1

Frequencies

GnomAD3 genomes AF: 0.217 AC: 33067 AN: 152108 Hom.: 3823 Cov.: 34

Gnomad AFR AF: 0.192

Gnomad AMI AF: 0.342

Gnomad AMR AF: 0.211

Gnomad ASJ AF: 0.135

Gnomad EAS AF: 0.152

Gnomad SAS AF: 0.0661

Gnomad FIN AF: 0.242

Gnomad MID AF: 0.101

Gnomad NFE AF: 0.250

Gnomad OTH AF: 0.198

GnomAD2 exomes AF: 0.202 AC: 50493 AN: 250192 AF XY: 0.195

Gnomad AFR exome AF: 0.192

Gnomad AMR exome AF: 0.228

Gnomad ASJ exome AF: 0.133

Gnomad EAS exome AF: 0.147

Gnomad FIN exome AF: 0.242

Gnomad NFE exome AF: 0.238

Gnomad OTH exome AF: 0.205

GnomAD4 exome AF: 0.231 AC: 336889 AN: 1459400 Hom.: 40947 Cov.: 34 AF XY: 0.225 AC XY: 163665 AN XY: 726026

African (AFR) AF: 0.189 AC: 6333 AN: 33452

American (AMR) AF: 0.226 AC: 10126 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.134 AC: 3501 AN: 26132

East Asian (EAS) AF: 0.128 AC: 5073 AN: 39694

South Asian (SAS) AF: 0.0723 AC: 6237 AN: 86244

European-Finnish (FIN) AF: 0.242 AC: 12648 AN: 52190

Middle Eastern (MID) AF: 0.0825 AC: 466 AN: 5648

European-Non Finnish (NFE) AF: 0.252 AC: 279770 AN: 1110994

Other (OTH) AF: 0.211 AC: 12735 AN: 60330

GnomAD4 genome AF: 0.217 AC: 33093 AN: 152226 Hom.: 3827 Cov.: 34 AF XY: 0.213 AC XY: 15834 AN XY: 74438

African (AFR) AF: 0.192 AC: 7960 AN: 41528

American (AMR) AF: 0.211 AC: 3228 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.135 AC: 467 AN: 3472

East Asian (EAS) AF: 0.152 AC: 788 AN: 5172

South Asian (SAS) AF: 0.0668 AC: 323 AN: 4834

European-Finnish (FIN) AF: 0.242 AC: 2566 AN: 10606

Middle Eastern (MID) AF: 0.109 AC: 32 AN: 294

European-Non Finnish (NFE) AF: 0.250 AC: 17004 AN: 67994

Other (OTH) AF: 0.196 AC: 414 AN: 2112

Alfa AF: 0.233 Hom.: 11615

Bravo AF: 0.218

Asia WGS AF: 0.102 AC: 357 AN: 3478

EpiCase AF: 0.229

EpiControl AF: 0.226

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
-	-	6	not specified (6)
-	-	4	Mucopolysaccharidosis type 1 (4)
-	-	3	not provided (3)
-	-	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
BayesDel_noAF	Benign	-0.78
CADD	Benign	6.2
DANN	Benign	0.60
PhyloP100		-0.11
Mutation Taster		=297/3	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: rs3755954; hg19: chr4-994452; COSMIC: COSV56102077; COSMIC: COSV56102077;