rs3755956

chr4-1000568-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000203.5(IDUA):c.300-44C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0379 in 1,451,130 control chromosomes in the GnomAD database, including 1,345 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.032 (125 hom., cov: 34)
  • Exomes 𝑓: 0.039 (1220 hom.)
• Consequence: IDUA NM_000203.5 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -1.77

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.87).
• BP6: Variant 4-1000568-C-T is Benign according to our data. Variant chr4-1000568-C-T is described in ClinVar as [Benign]. Clinvar id is 255526.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.111 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
IDUA	NM_000203.5	c.300-44C>T		intron_variant		ENST00000514224.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
IDUA	ENST00000514224.2	c.300-44C>T		intron_variant		2	NM_000203.5	P1

Frequencies

GnomAD3 genomes AF: 0.0323 AC: 4915 AN: 152238 Hom.: 124 Cov.: 34

Gnomad AFR AF: 0.0110

Gnomad AMI AF: 0.00329

Gnomad AMR AF: 0.0327

Gnomad ASJ AF: 0.0161

Gnomad EAS AF: 0.119

Gnomad SAS AF: 0.0170

Gnomad FIN AF: 0.0490

Gnomad MID AF: 0.0316

Gnomad NFE AF: 0.0377

Gnomad OTH AF: 0.0507

GnomAD3 exomes AF: 0.0372 AC: 9248 AN: 248650 Hom.: 261 AF XY: 0.0361 AC XY: 4877 AN XY: 135152

Gnomad AFR exome AF: 0.00949

Gnomad AMR exome AF: 0.0199

Gnomad ASJ exome AF: 0.0155

Gnomad EAS exome AF: 0.119

Gnomad SAS exome AF: 0.0136

Gnomad FIN exome AF: 0.0516

Gnomad NFE exome AF: 0.0385

Gnomad OTH exome AF: 0.0385

GnomAD4 exome AF: 0.0385 AC: 50030 AN: 1298774 Hom.: 1220 Cov.: 19 AF XY: 0.0376 AC XY: 24643 AN XY: 654688

Gnomad4 AFR exome AF: 0.00954

Gnomad4 AMR exome AF: 0.0209

Gnomad4 ASJ exome AF: 0.0137

Gnomad4 EAS exome AF: 0.114

Gnomad4 SAS exome AF: 0.0137

Gnomad4 FIN exome AF: 0.0531

Gnomad4 NFE exome AF: 0.0392

Gnomad4 OTH exome AF: 0.0404

GnomAD4 genome AF: 0.0323 AC: 4919 AN: 152356 Hom.: 125 Cov.: 34 AF XY: 0.0327 AC XY: 2433 AN XY: 74508

Gnomad4 AFR AF: 0.0109

Gnomad4 AMR AF: 0.0327

Gnomad4 ASJ AF: 0.0161

Gnomad4 EAS AF: 0.119

Gnomad4 SAS AF: 0.0170

Gnomad4 FIN AF: 0.0490

Gnomad4 NFE AF: 0.0377

Gnomad4 OTH AF: 0.0544

Alfa AF: 0.0313 Hom.: 14

Bravo AF: 0.0315

Asia WGS AF: 0.0730 AC: 254 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

-

- -

Mucopolysaccharidosis type 1 Benign:1

Benign, no assertion criteria provided

clinical testing

Natera, Inc.

Apr 13, 2018

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Jul 09, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
Cadd	Benign	0.42
Dann	Benign	0.53

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: rs3755956; hg19: chr4-994356; COSMIC: COSV56104596; COSMIC: COSV56104596;