4-1002772-C-G

Variant names:

• chr4-1002772-C-G
• rs115790973
• NM_000203.5:c.1230C>G

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.1230C>G variant in IDUA is a synonymous (silent) variant (p.Thr410=). The Grpmax Filtering AF (95% confidence) in gnomAD v4.1.0 is 0.2954 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: 92628). 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/CA145870/MONDO:0001586/091

• Frequency:
  • Genomes: 𝑓 0.17 (2327 hom., cov: 32)
  • Exomes 𝑓: 0.16 (18473 hom.)
• Consequence: IDUA NM_000203.5 synonymous
• Clinical Significance: Benign reviewed by expert panel B:12
• Conservation: PhyloP100: -1.80
• 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: ClinGen, Myriad Women’s Health
• Scheie syndrome

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

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.1230C>G	p.Thr410Thr	synonymous	Exon 9 of 14	NP_000194.2
	IDUA	NM_001363576.1		c.834C>G	p.Thr278Thr	synonymous	Exon 8 of 13	NP_001350505.1
	IDUA	NR_110313.1		n.1318C>G		non_coding_transcript_exon	Exon 9 of 14

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IDUA	ENST00000514224.2	TSL:2 MANE Select	c.1230C>G	p.Thr410Thr	synonymous	Exon 9 of 14	ENSP00000425081.2
	IDUA	ENST00000247933.9	TSL:1	c.1230C>G	p.Thr410Thr	synonymous	Exon 9 of 14	ENSP00000247933.4
	IDUA	ENST00000962389.1		c.1305C>G	p.Thr435Thr	synonymous	Exon 10 of 15	ENSP00000632448.1

Frequencies

GnomAD3 genomes AF: 0.172 AC: 25972 AN: 151430 Hom.: 2331 Cov.: 32

Gnomad AFR AF: 0.211

Gnomad AMI AF: 0.171

Gnomad AMR AF: 0.123

Gnomad ASJ AF: 0.166

Gnomad EAS AF: 0.199

Gnomad SAS AF: 0.302

Gnomad FIN AF: 0.142

Gnomad MID AF: 0.236

Gnomad NFE AF: 0.152

Gnomad OTH AF: 0.182

GnomAD2 exomes AF: 0.174 AC: 14580 AN: 83954 AF XY: 0.190

Gnomad AFR exome AF: 0.208

Gnomad AMR exome AF: 0.0740

Gnomad ASJ exome AF: 0.161

Gnomad EAS exome AF: 0.221

Gnomad FIN exome AF: 0.156

Gnomad NFE exome AF: 0.158

Gnomad OTH exome AF: 0.174

GnomAD4 exome AF: 0.161 AC: 212281 AN: 1321686 Hom.: 18473 Cov.: 36 AF XY: 0.165 AC XY: 107188 AN XY: 651162

African (AFR) AF: 0.220 AC: 5877 AN: 26738

American (AMR) AF: 0.0863 AC: 2406 AN: 27868

Ashkenazi Jewish (ASJ) AF: 0.160 AC: 3735 AN: 23360

East Asian (EAS) AF: 0.160 AC: 4660 AN: 29150

South Asian (SAS) AF: 0.298 AC: 21640 AN: 72516

European-Finnish (FIN) AF: 0.158 AC: 5263 AN: 33272

Middle Eastern (MID) AF: 0.220 AC: 861 AN: 3916

European-Non Finnish (NFE) AF: 0.151 AC: 158602 AN: 1049976

Other (OTH) AF: 0.168 AC: 9237 AN: 54890

GnomAD4 genome AF: 0.171 AC: 25969 AN: 151538 Hom.: 2327 Cov.: 32 AF XY: 0.172 AC XY: 12705 AN XY: 74072

African (AFR) AF: 0.210 AC: 8697 AN: 41320

American (AMR) AF: 0.123 AC: 1877 AN: 15270

Ashkenazi Jewish (ASJ) AF: 0.166 AC: 575 AN: 3472

East Asian (EAS) AF: 0.199 AC: 1012 AN: 5096

South Asian (SAS) AF: 0.301 AC: 1444 AN: 4792

European-Finnish (FIN) AF: 0.142 AC: 1488 AN: 10512

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

European-Non Finnish (NFE) AF: 0.152 AC: 10270 AN: 67758

Other (OTH) AF: 0.181 AC: 383 AN: 2116

Alfa AF: 0.0617 Hom.: 73

Bravo AF: 0.169

Asia WGS AF: 0.249 AC: 865 AN: 3452

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)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.79
CADD	Benign	1.6
DANN	Benign	0.50
PhyloP100		-1.8
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs115790973; hg19: chr4-996560;