rs6815946

Variant names:

• chr4-1001517-T-C
• rs6815946
• NM_000203.5:c.543T>C

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.543T>C variant in IDUA is a synonymous (silent) variant (p.Asn181=). The Grpmax Filtering AF (95% confidence) in gnomAD v4.1.0 is 0.2950 in the South Asian population. This 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: 92645). 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 January 2, 2025) LINK:https://erepo.genome.network/evrepo/ui/classification/CA145885/MONDO:0001586/091

• Frequency:
  • Genomes: 𝑓 0.17 (2398 hom., cov: 33)
  • Exomes 𝑓: 0.16 (20855 hom.)
• Consequence: IDUA NM_000203.5 synonymous
• Clinical Significance: Benign reviewed by expert panel B:15
• Conservation: PhyloP100: -1.19
• Publications: 32 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.543T>C	p.Asn181Asn	synonymous	Exon 5 of 14	NP_000194.2	P35475-1
	IDUA	NM_001363576.1		c.147T>C	p.Asn49Asn	synonymous	Exon 4 of 13	NP_001350505.1
	IDUA	NR_110313.1		n.631T>C		non_coding_transcript_exon	Exon 5 of 14

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IDUA	ENST00000514224.2	TSL:2 MANE Select	c.543T>C	p.Asn181Asn	synonymous	Exon 5 of 14	ENSP00000425081.2	P35475-1
	IDUA	ENST00000247933.9	TSL:1	c.543T>C	p.Asn181Asn	synonymous	Exon 5 of 14	ENSP00000247933.4	P35475-1
	IDUA	ENST00000962389.1		c.618T>C	p.Asn206Asn	synonymous	Exon 6 of 15	ENSP00000632448.1

Frequencies

GnomAD3 genomes AF: 0.173 AC: 26368 AN: 152000 Hom.: 2402 Cov.: 33

Gnomad AFR AF: 0.215

Gnomad AMI AF: 0.171

Gnomad AMR AF: 0.124

Gnomad ASJ AF: 0.166

Gnomad EAS AF: 0.199

Gnomad SAS AF: 0.300

Gnomad FIN AF: 0.145

Gnomad MID AF: 0.234

Gnomad NFE AF: 0.153

Gnomad OTH AF: 0.182

GnomAD2 exomes AF: 0.173 AC: 43316 AN: 250892 AF XY: 0.181

Gnomad AFR exome AF: 0.217

Gnomad AMR exome AF: 0.0788

Gnomad ASJ exome AF: 0.160

Gnomad EAS exome AF: 0.213

Gnomad FIN exome AF: 0.147

Gnomad NFE exome AF: 0.160

Gnomad OTH exome AF: 0.174

GnomAD4 exome AF: 0.162 AC: 237274 AN: 1460884 Hom.: 20855 Cov.: 34 AF XY: 0.167 AC XY: 121007 AN XY: 726742

African (AFR) AF: 0.223 AC: 7459 AN: 33480

American (AMR) AF: 0.0844 AC: 3773 AN: 44714

Ashkenazi Jewish (ASJ) AF: 0.161 AC: 4199 AN: 26134

East Asian (EAS) AF: 0.171 AC: 6794 AN: 39700

South Asian (SAS) AF: 0.298 AC: 25689 AN: 86256

European-Finnish (FIN) AF: 0.152 AC: 8007 AN: 52558

Middle Eastern (MID) AF: 0.204 AC: 1174 AN: 5768

European-Non Finnish (NFE) AF: 0.153 AC: 170010 AN: 1111890

Other (OTH) AF: 0.168 AC: 10169 AN: 60384

GnomAD4 genome AF: 0.173 AC: 26365 AN: 152118 Hom.: 2398 Cov.: 33 AF XY: 0.173 AC XY: 12899 AN XY: 74366

African (AFR) AF: 0.214 AC: 8890 AN: 41464

American (AMR) AF: 0.123 AC: 1889 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.166 AC: 576 AN: 3472

East Asian (EAS) AF: 0.199 AC: 1026 AN: 5162

South Asian (SAS) AF: 0.300 AC: 1446 AN: 4824

European-Finnish (FIN) AF: 0.145 AC: 1533 AN: 10600

Middle Eastern (MID) AF: 0.228 AC: 67 AN: 294

European-Non Finnish (NFE) AF: 0.153 AC: 10401 AN: 67974

Other (OTH) AF: 0.181 AC: 381 AN: 2110

Alfa AF: 0.160 Hom.: 7427

Bravo AF: 0.171

Asia WGS AF: 0.246 AC: 859 AN: 3478

EpiCase AF: 0.159

EpiControl AF: 0.165

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)
-	-	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	-0.66
CADD	Benign	0.60
DANN	Benign	0.63
PhyloP100		-1.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=99/1	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs6815946; hg19: chr4-995305; COSMIC: COSV56102644; COSMIC: COSV56102644;