4-1001671-C-T

Variant names:

• chr4-1001671-C-T
• rs6848974
• NM_000203.5:c.590-8C>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.590-8C>T variant is a nucleotide substitution in the acceptor splice site region of intron 5 of IDUA. The highest population minor allele frequency in gnomAD v4.1.0 is 0.2984 (27112/90864 alleles; 4285 homozygotes; Grpmax Filtering AF 95% confidence = 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: 92646). 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/CA145887/MONDO:0001586/091

• Frequency:
  • Genomes: 𝑓 0.17 (2376 hom., cov: 33)
  • Exomes 𝑓: 0.16 (20716 hom.)
• Consequence: IDUA NM_000203.5 splice_region, intron
• Scores: Splicing: ADA: 0.00006631
• Clinical Significance: Benign reviewed by expert panel B:16
• Conservation: PhyloP100: -0.00700
• Publications: 13 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.590-8C>T		splice_region intron	N/A	NP_000194.2	P35475-1
	IDUA	NM_001363576.1		c.194-8C>T		splice_region intron	N/A	NP_001350505.1
	IDUA	NR_110313.1		n.678-8C>T		splice_region intron	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IDUA	ENST00000514224.2	TSL:2 MANE Select	c.590-8C>T		splice_region intron	N/A	ENSP00000425081.2	P35475-1
	IDUA	ENST00000247933.9	TSL:1	c.590-8C>T		splice_region intron	N/A	ENSP00000247933.4	P35475-1
	IDUA	ENST00000962389.1		c.665-8C>T		splice_region intron	N/A	ENSP00000632448.1

Frequencies

GnomAD3 genomes AF: 0.173 AC: 26284 AN: 152010 Hom.: 2380 Cov.: 33

Gnomad AFR AF: 0.213

Gnomad AMI AF: 0.169

Gnomad AMR AF: 0.124

Gnomad ASJ AF: 0.166

Gnomad EAS AF: 0.200

Gnomad SAS AF: 0.301

Gnomad FIN AF: 0.144

Gnomad MID AF: 0.234

Gnomad NFE AF: 0.153

Gnomad OTH AF: 0.182

GnomAD2 exomes AF: 0.176 AC: 40992 AN: 233562 AF XY: 0.184

Gnomad AFR exome AF: 0.217

Gnomad AMR exome AF: 0.0790

Gnomad ASJ exome AF: 0.160

Gnomad EAS exome AF: 0.215

Gnomad FIN exome AF: 0.155

Gnomad NFE exome AF: 0.162

Gnomad OTH exome AF: 0.175

GnomAD4 exome AF: 0.163 AC: 235600 AN: 1449094 Hom.: 20716 Cov.: 34 AF XY: 0.167 AC XY: 120254 AN XY: 721078

African (AFR) AF: 0.220 AC: 7352 AN: 33376

American (AMR) AF: 0.0844 AC: 3742 AN: 44350

Ashkenazi Jewish (ASJ) AF: 0.160 AC: 4181 AN: 26074

East Asian (EAS) AF: 0.171 AC: 6773 AN: 39494

South Asian (SAS) AF: 0.298 AC: 25662 AN: 86034

European-Finnish (FIN) AF: 0.155 AC: 6773 AN: 43616

Middle Eastern (MID) AF: 0.203 AC: 1171 AN: 5758

European-Non Finnish (NFE) AF: 0.153 AC: 169766 AN: 1110212

Other (OTH) AF: 0.169 AC: 10180 AN: 60180

GnomAD4 genome AF: 0.173 AC: 26281 AN: 152128 Hom.: 2376 Cov.: 33 AF XY: 0.173 AC XY: 12863 AN XY: 74382

African (AFR) AF: 0.212 AC: 8805 AN: 41478

American (AMR) AF: 0.123 AC: 1888 AN: 15302

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

East Asian (EAS) AF: 0.200 AC: 1033 AN: 5172

South Asian (SAS) AF: 0.300 AC: 1450 AN: 4830

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

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

European-Non Finnish (NFE) AF: 0.153 AC: 10399 AN: 67950

Other (OTH) AF: 0.181 AC: 382 AN: 2112

Alfa AF: 0.132 Hom.: 709

Bravo AF: 0.170

ClinVar

ClinVar submissions

Significance: Benign

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
-	-	5	not specified (5)
-	-	4	Mucopolysaccharidosis type 1 (4)
-	-	4	not provided (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
BayesDel_noAF	Benign	-0.82
CADD	Benign	1.0
DANN	Benign	0.63
PhyloP100		-0.0070
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000066
dbscSNV1_RF	Benign	0.0020
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: rs6848974; hg19: chr4-995459; COSMIC: COSV56105806; COSMIC: COSV56105806;