4-1000626-G-A

Variant names:

• chr4-1000626-G-A
• rs3755955
• NM_000203.5:c.314G>A

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.314G>A variant in IDUA is a missense variant predicted to cause substitution of arginine by glutamine at amino acid 105 (p.Arg105Gln). The highest population minor allele frequency in gnomAD v4.1.0 is 0.2431 (22127/91024 alleles; 2838 homozygotes; Grpmax Filtering AF 95% confidence = 0.2404) 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: 92641). 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/CA145881/MONDO:0001586/091

• Frequency:
  • Genomes: 𝑓 0.14 (1595 hom., cov: 34)
  • Exomes 𝑓: 0.15 (18412 hom.)
• Consequence: IDUA NM_000203.5 missense
• Clinical Significance: Benign reviewed by expert panel B:17
• Conservation: PhyloP100: 0.235
• Publications: 92 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.314G>A	p.Arg105Gln	missense	Exon 3 of 14	NP_000194.2	P35475-1
	IDUA	NM_001363576.1		c.-83G>A		5_prime_UTR	Exon 2 of 13	NP_001350505.1
	IDUA	NR_110313.1		n.402G>A		non_coding_transcript_exon	Exon 3 of 14

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IDUA	ENST00000514224.2	TSL:2 MANE Select	c.314G>A	p.Arg105Gln	missense	Exon 3 of 14	ENSP00000425081.2	P35475-1
	IDUA	ENST00000247933.9	TSL:1	c.314G>A	p.Arg105Gln	missense	Exon 3 of 14	ENSP00000247933.4	P35475-1
	IDUA	ENST00000962389.1		c.389G>A	p.Arg130Gln	missense	Exon 4 of 15	ENSP00000632448.1

Frequencies

GnomAD3 genomes AF: 0.142 AC: 21587 AN: 152130 Hom.: 1599 Cov.: 34

Gnomad AFR AF: 0.116

Gnomad AMI AF: 0.171

Gnomad AMR AF: 0.107

Gnomad ASJ AF: 0.164

Gnomad EAS AF: 0.193

Gnomad SAS AF: 0.242

Gnomad FIN AF: 0.144

Gnomad MID AF: 0.225

Gnomad NFE AF: 0.152

Gnomad OTH AF: 0.150

GnomAD2 exomes AF: 0.157 AC: 39334 AN: 250258 AF XY: 0.165

Gnomad AFR exome AF: 0.117

Gnomad AMR exome AF: 0.0721

Gnomad ASJ exome AF: 0.157

Gnomad EAS exome AF: 0.211

Gnomad FIN exome AF: 0.147

Gnomad NFE exome AF: 0.159

Gnomad OTH exome AF: 0.162

GnomAD4 exome AF: 0.154 AC: 225302 AN: 1458656 Hom.: 18412 Cov.: 32 AF XY: 0.157 AC XY: 114263 AN XY: 725732

African (AFR) AF: 0.116 AC: 3881 AN: 33448

American (AMR) AF: 0.0760 AC: 3397 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.157 AC: 4114 AN: 26124

East Asian (EAS) AF: 0.158 AC: 6286 AN: 39684

South Asian (SAS) AF: 0.243 AC: 20955 AN: 86200

European-Finnish (FIN) AF: 0.152 AC: 7947 AN: 52172

Middle Eastern (MID) AF: 0.189 AC: 1085 AN: 5726

European-Non Finnish (NFE) AF: 0.152 AC: 168293 AN: 1110274

Other (OTH) AF: 0.155 AC: 9344 AN: 60312

GnomAD4 genome AF: 0.142 AC: 21578 AN: 152248 Hom.: 1595 Cov.: 34 AF XY: 0.142 AC XY: 10588 AN XY: 74438

African (AFR) AF: 0.116 AC: 4813 AN: 41556

American (AMR) AF: 0.107 AC: 1638 AN: 15310

Ashkenazi Jewish (ASJ) AF: 0.164 AC: 569 AN: 3472

East Asian (EAS) AF: 0.192 AC: 993 AN: 5166

South Asian (SAS) AF: 0.243 AC: 1172 AN: 4824

European-Finnish (FIN) AF: 0.144 AC: 1528 AN: 10608

Middle Eastern (MID) AF: 0.221 AC: 65 AN: 294

European-Non Finnish (NFE) AF: 0.152 AC: 10334 AN: 67996

Other (OTH) AF: 0.147 AC: 310 AN: 2110

Alfa AF: 0.149 Hom.: 7164

Bravo AF: 0.136

TwinsUK AF: 0.165 AC: 612

ALSPAC AF: 0.159 AC: 611

ESP6500AA AF: 0.107 AC: 473

ESP6500EA AF: 0.160 AC: 1376

ExAC AF: 0.163 AC: 19766

Asia WGS AF: 0.194 AC: 679 AN: 3478

EpiCase AF: 0.157

EpiControl AF: 0.163

ClinVar

ClinVar submissions

Significance: Benign

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
-	-	5	not provided (5)
-	-	5	not specified (5)
-	-	4	Mucopolysaccharidosis type 1 (4)
-	-	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
AlphaMissense	Benign	0.067
BayesDel_addAF	Benign	-0.46	T
BayesDel_noAF	Benign	-0.29
CADD	Benign	0.74
DANN	Benign	0.77
DEOGEN2	Uncertain	0.46	T
Eigen	Benign	-1.6
Eigen_PC	Benign	-1.5
FATHMM_MKL	Benign	0.035	N
LIST_S2	Benign	0.41	T
MetaRNN	Benign	0.0045	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-0.91	N
PhyloP100		0.23
PrimateAI	Benign	0.20	T
PROVEAN	Benign	0.050	N
REVEL	Uncertain	0.32
Sift	Benign	1.0	T
Sift4G	Benign	0.72	T
Polyphen		0.0030	B
Vest4		0.019
MPC		0.22
ClinPred		0.000033	T
GERP RS		1.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.056
gMVP		0.55
Mutation Taster		=96/4	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: rs3755955; hg19: chr4-994414; COSMIC: COSV56105630; COSMIC: COSV56105630;