4-1002713-GCCC-GCCCC

Position:

• chr4-1002713-GCCC-GCCCC

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP6_Very_Strong BA1

The NM_000203.5(IDUA):​c.1190-10dup variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.164 in 149,514 control chromosomes in the GnomAD database, including 2,046 homozygotes. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.16 (2046 hom., cov: 29)
  • Exomes 𝑓: 0.093 (3064 hom.)
  • Failed GnomAD Quality Control
• Consequence: IDUA NM_000203.5 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: -0.792

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]

ACMG classification

Verdict is Benign. Variant got -16 ACMG points.

• BP6: Variant 4-1002713-G-GC is Benign according to our data. Variant chr4-1002713-G-GC is described in ClinVar as [Benign]. Clinvar id is 92626.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.283 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
IDUA	NM_000203.5	c.1190-10dup		intron_variant		ENST00000514224.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
IDUA	ENST00000514224.2	c.1190-10dup		intron_variant		2	NM_000203.5	P1

Frequencies

GnomAD3 genomes AF: 0.164 AC: 24511 AN: 149414 Hom.: 2051 Cov.: 29

Gnomad AFR AF: 0.192

Gnomad AMI AF: 0.158

Gnomad AMR AF: 0.122

Gnomad ASJ AF: 0.167

Gnomad EAS AF: 0.192

Gnomad SAS AF: 0.297

Gnomad FIN AF: 0.136

Gnomad MID AF: 0.222

Gnomad NFE AF: 0.149

Gnomad OTH AF: 0.175

GnomAD3 exomes AF: 0.160 AC: 11726 AN: 73188 Hom.: 595 AF XY: 0.174 AC XY: 7220 AN XY: 41468

Gnomad AFR exome AF: 0.172

Gnomad AMR exome AF: 0.0747

Gnomad ASJ exome AF: 0.154

Gnomad EAS exome AF: 0.195

Gnomad SAS exome AF: 0.266

Gnomad FIN exome AF: 0.147

Gnomad NFE exome AF: 0.148

Gnomad OTH exome AF: 0.169

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.0927 AC: 110358 AN: 1190586 Hom.: 3064 Cov.: 24 AF XY: 0.0998 AC XY: 58876 AN XY: 590056

Gnomad4 AFR exome AF: 0.118

Gnomad4 AMR exome AF: 0.0725

Gnomad4 ASJ exome AF: 0.127

Gnomad4 EAS exome AF: 0.126

Gnomad4 SAS exome AF: 0.231

Gnomad4 FIN exome AF: 0.141

Gnomad4 NFE exome AF: 0.0784

Gnomad4 OTH exome AF: 0.106

GnomAD4 genome AF: 0.164 AC: 24506 AN: 149514 Hom.: 2046 Cov.: 29 AF XY: 0.164 AC XY: 11960 AN XY: 72964

Gnomad4 AFR AF: 0.192

Gnomad4 AMR AF: 0.121

Gnomad4 ASJ AF: 0.167

Gnomad4 EAS AF: 0.192

Gnomad4 SAS AF: 0.296

Gnomad4 FIN AF: 0.136

Gnomad4 NFE AF: 0.149

Gnomad4 OTH AF: 0.174

ClinVar

Significance: Benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jul 17, 2012	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	GeneDx	Sep 17, 2018	- -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jan 15, 2016	Variant summary: The c.1190-10dupC variant affects a intronic polyC site. One in-silico tool predicts benign outcome for this variant. 5/5 programs in Alamut predict that this variant does not affect normal splicing. This variant is found in 1655/7502 control chromosomes (116 homozygotes) at a frequency of 0.2206078, which is about 82 times of maximal expected frequency of a pathogenic allele (0.0026926), suggesting this variant is benign. In addition, one clinical laboratory classified this variant as bengin. Taken together, this variant was classified as benign. -
Benign, no assertion criteria provided	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Feb 02, 2016	- -

Mucopolysaccharidosis type 1 Benign:2

Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -

Computational scores

Source: dbNSFP v4.3

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

Publications

LitVar

Other links and lift over

dbSNP: rs150523349; hg19: chr4-996501;