4-1003100-C-T

Variant names:

• chr4-1003100-C-T
• rs115929690
• NM_000203.5:c.1467C>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.1467C>T variant in IDUA is a synonymous (silent) variant (p.Arg489=). The highest population minor allele frequency in gnomAD v4.1.0 is 0.2948 (23904/81086 alleles; 3762 homozygotes; Grpmax Filtering AF 95% confidence = 0.2917) 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: 92632). 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 Disorders 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/CA145874/MONDO:0001586/091

• Frequency:
  • Genomes: 𝑓 0.17 (2355 hom., cov: 33)
  • Exomes 𝑓: 0.16 (19025 hom.)
• Consequence: IDUA NM_000203.5 synonymous
• Clinical Significance: Benign reviewed by expert panel B:13
• Conservation: PhyloP100: -0.905
• Publications: 15 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: Myriad Women’s Health, ClinGen
• Scheie syndrome

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

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IDUA	NM_000203.5	MANE Select	c.1467C>T	p.Arg489Arg	synonymous	Exon 10 of 14	NP_000194.2	P35475-1
	IDUA	NM_001363576.1		c.1071C>T	p.Arg357Arg	synonymous	Exon 9 of 13	NP_001350505.1
	IDUA	NR_110313.1		n.1555C>T		non_coding_transcript_exon	Exon 10 of 14

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IDUA	ENST00000514224.2	TSL:2 MANE Select	c.1467C>T	p.Arg489Arg	synonymous	Exon 10 of 14	ENSP00000425081.2	P35475-1
	IDUA	ENST00000247933.9	TSL:1	c.1467C>T	p.Arg489Arg	synonymous	Exon 10 of 14	ENSP00000247933.4	P35475-1
	IDUA	ENST00000962389.1		c.1542C>T	p.Arg514Arg	synonymous	Exon 11 of 15	ENSP00000632448.1

Frequencies

GnomAD3 genomes AF: 0.172 AC: 26134 AN: 151710 Hom.: 2359 Cov.: 33

Gnomad AFR AF: 0.212

Gnomad AMI AF: 0.170

Gnomad AMR AF: 0.124

Gnomad ASJ AF: 0.165

Gnomad EAS AF: 0.201

Gnomad SAS AF: 0.299

Gnomad FIN AF: 0.144

Gnomad MID AF: 0.236

Gnomad NFE AF: 0.152

Gnomad OTH AF: 0.183

GnomAD2 exomes AF: 0.174 AC: 25755 AN: 148148 AF XY: 0.186

Gnomad AFR exome AF: 0.220

Gnomad AMR exome AF: 0.0699

Gnomad ASJ exome AF: 0.159

Gnomad EAS exome AF: 0.216

Gnomad FIN exome AF: 0.157

Gnomad NFE exome AF: 0.163

Gnomad OTH exome AF: 0.175

GnomAD4 exome AF: 0.161 AC: 218886 AN: 1362958 Hom.: 19025 Cov.: 37 AF XY: 0.165 AC XY: 111298 AN XY: 676220

African (AFR) AF: 0.220 AC: 6250 AN: 28416

American (AMR) AF: 0.0799 AC: 2721 AN: 34054

Ashkenazi Jewish (ASJ) AF: 0.160 AC: 3817 AN: 23928

East Asian (EAS) AF: 0.162 AC: 5099 AN: 31398

South Asian (SAS) AF: 0.295 AC: 22463 AN: 76256

European-Finnish (FIN) AF: 0.158 AC: 5584 AN: 35346

Middle Eastern (MID) AF: 0.203 AC: 1107 AN: 5462

European-Non Finnish (NFE) AF: 0.152 AC: 162435 AN: 1071866

Other (OTH) AF: 0.167 AC: 9410 AN: 56232

GnomAD4 genome AF: 0.172 AC: 26131 AN: 151818 Hom.: 2355 Cov.: 33 AF XY: 0.172 AC XY: 12796 AN XY: 74224

African (AFR) AF: 0.212 AC: 8776 AN: 41432

American (AMR) AF: 0.123 AC: 1883 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.165 AC: 571 AN: 3460

East Asian (EAS) AF: 0.200 AC: 1027 AN: 5128

South Asian (SAS) AF: 0.298 AC: 1441 AN: 4830

European-Finnish (FIN) AF: 0.144 AC: 1515 AN: 10530

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

European-Non Finnish (NFE) AF: 0.152 AC: 10313 AN: 67852

Other (OTH) AF: 0.182 AC: 384 AN: 2108

Alfa AF: 0.151 Hom.: 236

Bravo AF: 0.169

Asia WGS AF: 0.248 AC: 861 AN: 3450

ClinVar

ClinVar submissions

Significance: Benign

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
-	-	5	not specified (5)
-	-	4	Mucopolysaccharidosis type 1 (4)
-	-	3	not provided (3)
-	-	1	Hurler syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.74
CADD	Benign	6.4
DANN	Benign	0.88
PhyloP100		-0.91
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=100/0	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: rs115929690; hg19: chr4-996888; COSMIC: COSV56103390; COSMIC: COSV56103390;