4-1001634-G-C

Variant names:

• chr4-1001634-G-C
• rs6829789
• NM_000203.5:c.590-45G>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000203.5(IDUA):​c.590-45G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.163 in 1,605,734 control chromosomes in the GnomAD database, including 23,077 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.17 (2374 hom., cov: 34)
  • Exomes 𝑓: 0.16 (20703 hom.)
• Consequence: IDUA NM_000203.5 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: -0.00500
• Publications: 7 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: Genomics England PanelApp, G2P, Labcorp Genetics (formerly Invitae), Orphanet
• 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: Genomics England PanelApp, Orphanet

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BP6: Variant 4-1001634-G-C is Benign according to our data. Variant chr4-1001634-G-C is described in ClinVar as Benign. ClinVar VariationId is 255528.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.287 is higher than 0.05.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IDUA	NM_000203.5	MANE Select	c.590-45G>C		intron	N/A	NP_000194.2
	IDUA	NM_001363576.1		c.194-45G>C		intron	N/A	NP_001350505.1
	IDUA	NR_110313.1		n.678-45G>C		intron	N/A

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IDUA	ENST00000514224.2	TSL:2 MANE Select	c.590-45G>C		intron	N/A	ENSP00000425081.2
	IDUA	ENST00000247933.9	TSL:1	c.590-45G>C		intron	N/A	ENSP00000247933.4
	IDUA	ENST00000502910.5	TSL:3	c.449-45G>C		intron	N/A	ENSP00000422952.1

Frequencies

GnomAD3 genomes AF: 0.173 AC: 26286 AN: 152066 Hom.: 2378 Cov.: 34

Gnomad AFR AF: 0.212

Gnomad AMI AF: 0.170

Gnomad AMR AF: 0.124

Gnomad ASJ AF: 0.166

Gnomad EAS AF: 0.199

Gnomad SAS AF: 0.300

Gnomad FIN AF: 0.144

Gnomad MID AF: 0.234

Gnomad NFE AF: 0.153

Gnomad OTH AF: 0.182

GnomAD2 exomes AF: 0.174 AC: 42032 AN: 241784 AF XY: 0.182

Gnomad AFR exome AF: 0.215

Gnomad AMR exome AF: 0.0786

Gnomad ASJ exome AF: 0.161

Gnomad EAS exome AF: 0.214

Gnomad FIN exome AF: 0.150

Gnomad NFE exome AF: 0.161

Gnomad OTH exome AF: 0.174

GnomAD4 exome AF: 0.162 AC: 235950 AN: 1453550 Hom.: 20703 Cov.: 32 AF XY: 0.166 AC XY: 120381 AN XY: 723228

African (AFR) AF: 0.220 AC: 7339 AN: 33410

American (AMR) AF: 0.0842 AC: 3747 AN: 44494

Ashkenazi Jewish (ASJ) AF: 0.160 AC: 4184 AN: 26096

East Asian (EAS) AF: 0.171 AC: 6783 AN: 39612

South Asian (SAS) AF: 0.298 AC: 25650 AN: 86132

European-Finnish (FIN) AF: 0.153 AC: 7384 AN: 48414

Middle Eastern (MID) AF: 0.203 AC: 1172 AN: 5766

European-Non Finnish (NFE) AF: 0.153 AC: 169512 AN: 1109396

Other (OTH) AF: 0.169 AC: 10179 AN: 60230

GnomAD4 genome AF: 0.173 AC: 26283 AN: 152184 Hom.: 2374 Cov.: 34 AF XY: 0.173 AC XY: 12863 AN XY: 74414

African (AFR) AF: 0.212 AC: 8807 AN: 41498

American (AMR) AF: 0.123 AC: 1888 AN: 15296

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

East Asian (EAS) AF: 0.198 AC: 1024 AN: 5164

South Asian (SAS) AF: 0.300 AC: 1447 AN: 4828

European-Finnish (FIN) AF: 0.144 AC: 1529 AN: 10618

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

European-Non Finnish (NFE) AF: 0.153 AC: 10408 AN: 67994

Other (OTH) AF: 0.181 AC: 383 AN: 2112

Alfa AF: 0.101 Hom.: 207

Bravo AF: 0.170

Asia WGS AF: 0.249 AC: 872 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Jul 05, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

not specified Benign:1

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Mucopolysaccharidosis, MPS-I-H/S Benign:1

Jul 10, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Mucopolysaccharidosis, MPS-I-S Benign:1

Jul 10, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Mucopolysaccharidosis type 1 Benign:1

Apr 13, 2018

Natera, Inc.

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Hurler syndrome Benign:1

Jul 10, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	0.73
DANN	Benign	0.74
PhyloP100		-0.0050
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.070		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: rs6829789; hg19: chr4-995422; COSMIC: COSV56104963; COSMIC: COSV56104963;