4-1002460-G-C

Variant names:

• chr4-1002460-G-C
• rs6836258
• NM_000203.5:c.1164G>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.1164G>C (p.Thr388=) variant is a synonymous (silent) variant. The highest population minor allele frequency in gnomAD v4.1.0 is 0.2976 (25114/84382 alleles; 3978 homozygotes; Grpmax Filtering AF 95% confidence = 0.2945) 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: 92625). In summary, this variant meets the criteria to be classified as benign for MPS I based on the 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/CA145867/MONDO:0001586/091

• Frequency:
  • Genomes: 𝑓 0.17 (2368 hom., cov: 34)
  • Exomes 𝑓: 0.16 (19662 hom.)
• Consequence: IDUA NM_000203.5 synonymous
• Clinical Significance: Benign reviewed by expert panel B:13
• Conservation: PhyloP100: -6.27
• Publications: 16 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.1164G>C	p.Thr388Thr	synonymous	Exon 8 of 14	NP_000194.2	P35475-1
	IDUA	NM_001363576.1		c.768G>C	p.Thr256Thr	synonymous	Exon 7 of 13	NP_001350505.1
	IDUA	NR_110313.1		n.1252G>C		non_coding_transcript_exon	Exon 8 of 14

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IDUA	ENST00000514224.2	TSL:2 MANE Select	c.1164G>C	p.Thr388Thr	synonymous	Exon 8 of 14	ENSP00000425081.2	P35475-1
	IDUA	ENST00000247933.9	TSL:1	c.1164G>C	p.Thr388Thr	synonymous	Exon 8 of 14	ENSP00000247933.4	P35475-1
	IDUA	ENST00000962389.1		c.1239G>C	p.Thr413Thr	synonymous	Exon 9 of 15	ENSP00000632448.1

Frequencies

GnomAD3 genomes AF: 0.173 AC: 26241 AN: 152064 Hom.: 2372 Cov.: 34

Gnomad AFR AF: 0.213

Gnomad AMI AF: 0.171

Gnomad AMR AF: 0.123

Gnomad ASJ AF: 0.166

Gnomad EAS AF: 0.201

Gnomad SAS AF: 0.300

Gnomad FIN AF: 0.144

Gnomad MID AF: 0.236

Gnomad NFE AF: 0.152

Gnomad OTH AF: 0.182

GnomAD2 exomes AF: 0.174 AC: 26448 AN: 151750 AF XY: 0.185

Gnomad AFR exome AF: 0.218

Gnomad AMR exome AF: 0.0822

Gnomad ASJ exome AF: 0.162

Gnomad EAS exome AF: 0.215

Gnomad FIN exome AF: 0.144

Gnomad NFE exome AF: 0.160

Gnomad OTH exome AF: 0.176

GnomAD4 exome AF: 0.161 AC: 225509 AN: 1398620 Hom.: 19662 Cov.: 35 AF XY: 0.165 AC XY: 113950 AN XY: 690122

African (AFR) AF: 0.222 AC: 6962 AN: 31402

American (AMR) AF: 0.0884 AC: 3175 AN: 35910

Ashkenazi Jewish (ASJ) AF: 0.161 AC: 4037 AN: 25070

East Asian (EAS) AF: 0.168 AC: 5993 AN: 35652

South Asian (SAS) AF: 0.297 AC: 23668 AN: 79560

European-Finnish (FIN) AF: 0.152 AC: 7225 AN: 47592

Middle Eastern (MID) AF: 0.199 AC: 1116 AN: 5616

European-Non Finnish (NFE) AF: 0.151 AC: 163540 AN: 1079858

Other (OTH) AF: 0.169 AC: 9793 AN: 57960

GnomAD4 genome AF: 0.172 AC: 26238 AN: 152180 Hom.: 2368 Cov.: 34 AF XY: 0.173 AC XY: 12844 AN XY: 74382

African (AFR) AF: 0.212 AC: 8817 AN: 41540

American (AMR) AF: 0.123 AC: 1883 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.166 AC: 575 AN: 3470

East Asian (EAS) AF: 0.201 AC: 1035 AN: 5158

South Asian (SAS) AF: 0.300 AC: 1446 AN: 4822

European-Finnish (FIN) AF: 0.144 AC: 1522 AN: 10590

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

European-Non Finnish (NFE) AF: 0.152 AC: 10354 AN: 67992

Other (OTH) AF: 0.181 AC: 383 AN: 2114

Alfa AF: 0.122 Hom.: 452

Bravo AF: 0.170

Asia WGS AF: 0.248 AC: 866 AN: 3474

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)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	0.017
DANN	Benign	0.63
PhyloP100		-6.3
Mutation Taster		=99/1	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs6836258; hg19: chr4-996248; COSMIC: COSV56104304; COSMIC: COSV56104304;