4-1002131-G-C

Variant names:

• chr4-1002131-G-C
• rs6830825
• NM_000203.5:c.942G>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.942G>C variant in IDUA is a synonymous (silent) variant (p.Ala314=). The Grpmax Filtering AF (95% confidence) in gnomAD v4.1.0 is 0.2937 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: 92650). 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/CA145892/MONDO:0001586/091

• Frequency:
  • Genomes: 𝑓 0.17 (2352 hom., cov: 33)
  • Exomes 𝑓: 0.16 (19683 hom.)
• Consequence: IDUA NM_000203.5 synonymous
• Clinical Significance: Benign reviewed by expert panel B:15
• Conservation: PhyloP100: -4.78
• Publications: 18 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

Specifications for IDUA are available in the ClinGen Criteria Specification Registry and recommended for reference when assigning criteria.

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.942G>C	p.Ala314Ala	synonymous	Exon 7 of 14	NP_000194.2	P35475-1
	IDUA	NM_001363576.1		c.546G>C	p.Ala182Ala	synonymous	Exon 6 of 13	NP_001350505.1
	IDUA	NR_110313.1		n.1030G>C		non_coding_transcript_exon	Exon 7 of 14

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IDUA	ENST00000514224.2	TSL:2 MANE Select	c.942G>C	p.Ala314Ala	synonymous	Exon 7 of 14	ENSP00000425081.2	P35475-1
	IDUA	ENST00000247933.9	TSL:1	c.942G>C	p.Ala314Ala	synonymous	Exon 7 of 14	ENSP00000247933.4	P35475-1
	IDUA	ENST00000962389.1		c.1017G>C	p.Ala339Ala	synonymous	Exon 8 of 15	ENSP00000632448.1

Frequencies

GnomAD3 genomes AF: 0.172 AC: 26198 AN: 152082 Hom.: 2356 Cov.: 33

Gnomad AFR AF: 0.212

Gnomad AMI AF: 0.171

Gnomad AMR AF: 0.124

Gnomad ASJ AF: 0.165

Gnomad EAS AF: 0.200

Gnomad SAS AF: 0.299

Gnomad FIN AF: 0.143

Gnomad MID AF: 0.234

Gnomad NFE AF: 0.152

Gnomad OTH AF: 0.182

GnomAD2 exomes AF: 0.172 AC: 28962 AN: 168596 AF XY: 0.181

Gnomad AFR exome AF: 0.215

Gnomad AMR exome AF: 0.0809

Gnomad ASJ exome AF: 0.161

Gnomad EAS exome AF: 0.209

Gnomad FIN exome AF: 0.144

Gnomad NFE exome AF: 0.157

Gnomad OTH exome AF: 0.173

GnomAD4 exome AF: 0.161 AC: 226832 AN: 1411856 Hom.: 19683 Cov.: 35 AF XY: 0.164 AC XY: 114702 AN XY: 697474

African (AFR) AF: 0.220 AC: 7153 AN: 32456

American (AMR) AF: 0.0868 AC: 3210 AN: 36988

Ashkenazi Jewish (ASJ) AF: 0.161 AC: 4057 AN: 25258

East Asian (EAS) AF: 0.168 AC: 6243 AN: 37118

South Asian (SAS) AF: 0.297 AC: 23860 AN: 80446

European-Finnish (FIN) AF: 0.151 AC: 7326 AN: 48560

Middle Eastern (MID) AF: 0.202 AC: 1152 AN: 5698

European-Non Finnish (NFE) AF: 0.151 AC: 163993 AN: 1086838

Other (OTH) AF: 0.168 AC: 9838 AN: 58494

GnomAD4 genome AF: 0.172 AC: 26195 AN: 152200 Hom.: 2352 Cov.: 33 AF XY: 0.172 AC XY: 12811 AN XY: 74396

African (AFR) AF: 0.212 AC: 8804 AN: 41542

American (AMR) AF: 0.123 AC: 1889 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.165 AC: 571 AN: 3468

East Asian (EAS) AF: 0.199 AC: 1027 AN: 5154

South Asian (SAS) AF: 0.299 AC: 1442 AN: 4822

European-Finnish (FIN) AF: 0.143 AC: 1520 AN: 10600

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

European-Non Finnish (NFE) AF: 0.152 AC: 10337 AN: 68000

Other (OTH) AF: 0.181 AC: 382 AN: 2110

Alfa AF: 0.153 Hom.: 625

Bravo AF: 0.169

Asia WGS AF: 0.249 AC: 871 AN: 3478

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	-0.91
CADD	Benign	0.54
DANN	Benign	0.29
PhyloP100		-4.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=97/3	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: rs6830825; hg19: chr4-995919; COSMIC: COSV56102732; COSMIC: COSV56102732;