4-1002713-GCCC-GCC

Position:

• chr4-1002713-GCCC-GCC

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP6_Very_Strong BS1 BS2

The NM_000203.5(IDUA):​c.1190-10del variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00392 in 1,358,110 control chromosomes in the GnomAD database, including 112 homozygotes. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.015 (51 hom., cov: 29)
  • Exomes 𝑓: 0.0025 (61 hom.)
• Consequence: IDUA NM_000203.5 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• 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-GC-G is Benign according to our data. Variant chr4-1002713-GC-G is described in ClinVar as [Benign]. Clinvar id is 496833.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr4-1002713-GC-G is described in Lovd as [Benign]. Variant chr4-1002713-GC-G is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0151 (2265/149774) while in subpopulation AFR AF= 0.0494 (2012/40716). AF 95% confidence interval is 0.0476. There are 51 homozygotes in gnomad4. There are 1056 alleles in male gnomad4 subpopulation. Median coverage is 29. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 51 AR gene

Transcripts

RefSeq

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

Ensembl

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

Frequencies

GnomAD3 genomes AF: 0.0151 AC: 2254 AN: 149676 Hom.: 49 Cov.: 29

Gnomad AFR AF: 0.0492

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00971

Gnomad ASJ AF: 0.00930

Gnomad EAS AF: 0.00119

Gnomad SAS AF: 0.000635

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00980

Gnomad NFE AF: 0.000595

Gnomad OTH AF: 0.0122

GnomAD3 exomes AF: 0.00548 AC: 401 AN: 73188 Hom.: 6 AF XY: 0.00417 AC XY: 173 AN XY: 41468

Gnomad AFR exome AF: 0.0564

Gnomad AMR exome AF: 0.00808

Gnomad ASJ exome AF: 0.0107

Gnomad EAS exome AF: 0.00741

Gnomad SAS exome AF: 0.00150

Gnomad FIN exome AF: 0.00140

Gnomad NFE exome AF: 0.00309

Gnomad OTH exome AF: 0.00954

GnomAD4 exome AF: 0.00253 AC: 3062 AN: 1208336 Hom.: 61 Cov.: 24 AF XY: 0.00221 AC XY: 1322 AN XY: 598660

Gnomad4 AFR exome AF: 0.0486

Gnomad4 AMR exome AF: 0.00654

Gnomad4 ASJ exome AF: 0.00812

Gnomad4 EAS exome AF: 0.00226

Gnomad4 SAS exome AF: 0.000787

Gnomad4 FIN exome AF: 0.000184

Gnomad4 NFE exome AF: 0.00113

Gnomad4 OTH exome AF: 0.00601

GnomAD4 genome AF: 0.0151 AC: 2265 AN: 149774 Hom.: 51 Cov.: 29 AF XY: 0.0144 AC XY: 1056 AN XY: 73100

Gnomad4 AFR AF: 0.0494

Gnomad4 AMR AF: 0.00970

Gnomad4 ASJ AF: 0.00930

Gnomad4 EAS AF: 0.00119

Gnomad4 SAS AF: 0.000424

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000595

Gnomad4 OTH AF: 0.0121

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jun 29, 2017	- -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Feb 19, 2023	Variant summary: IDUA c.1190-10delC alters a non-conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. 4/4 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 0.0055 in 73188 control chromosomes in the gnomAD database, including 6 homozygotes. The observed variant frequency is approximately 2 fold of the estimated maximal expected allele frequency for a pathogenic variant in IDUA causing Mucopolysaccharidosis Type 1 phenotype (0.0027), strongly suggesting that the variant is benign. To our knowledge, no occurrence of c.1190-10delC in individuals affected with Mucopolysaccharidosis Type 1 and no experimental evidence demonstrating its impact on protein function have been reported. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and all classified the variant as benign. Based on the evidence outlined above, the variant was classified as benign. -

Mucopolysaccharidosis type 1 Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Feb 01, 2024

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Oct 28, 2019

- -

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;