4-987108-C-A

Variant names:

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BA1

This summary comes from the ClinGen Evidence Repository: The NM_000203.5:c.24C>A variant in IDUA is a synonymous (silent) variant (p.Ala8=). The Grpmax Filtering AF (95% confidence) in gnomAD v4.1.0 is 0.5236 in the Admixed American population. This 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: 92638). In summary, this variant meets the criteria to be classified as benign for mucopolysaccharidosis type 1. IDUA-specific 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 January 2, 2025) LINK:https://erepo.genome.network/evrepo/ui/classification/CA145878/MONDO:0001586/091

Frequency

Genomes: 𝑓 0.40 ( 12365 hom., cov: 35)

Exomes 𝑓: 0.43 ( 119539 hom. )

Consequence

IDUA
NM_000203.5 synonymous

Scores

Clinical Significance

Benign reviewed by expert panel B:13

Conservation

PhyloP100: -0.0790

Variant links:

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 links:

SLC26A1 (HGNC:10993): (solute carrier family 26 member 1) This gene is a member of a family of sulfate/anion transporter genes. Family members are well conserved in their genomic (number and size of exons) and protein (aa length among species) structures, but have markedly different tissue expression patterns. This gene is primarily expressed in the liver, pancreas, and brain. Three splice variants that encode different isoforms have been identified. [provided by RefSeq, Jul 2008]

SLC26A1 links:

DGKQ (HGNC:2856): (diacylglycerol kinase theta) The protein encoded by this gene contains three cysteine-rich domains, a proline-rich region, and a pleckstrin homology domain with an overlapping Ras-associating domain. It is localized in the speckle domains of the nucleus, and mediates the regeneration of phosphatidylinositol (PI) from diacylglycerol in the PI-cycle during cell signal transduction. [provided by RefSeq, Jul 2008]

DGKQ links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -8 ACMG points.

BA1

For more information check the summary or visit ClinGen Evidence Repository.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
IDUA	NM_000203.5 link	c.24C>A	p.Ala8Ala	synonymous_variant	Exon 1 of 14	ENST00000514224.2	NP_000194.2	P35475-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
IDUA	ENST00000514224.2 link	c.24C>A	p.Ala8Ala	synonymous_variant	Exon 1 of 14	2	NM_000203.5	ENSP00000425081.2		P35475-1

Frequencies

GnomAD3 genomes

AF:

0.399

AC:

60531

AN:

151804

Hom.:

12356

Cov.:

show subpopulations

Gnomad AFR

AF:

0.332

Gnomad AMI

AF:

0.259

Gnomad AMR

AF:

0.484

Gnomad ASJ

AF:

0.367

Gnomad EAS

AF:

0.278

Gnomad SAS

AF:

0.437

Gnomad FIN

AF:

0.435

Gnomad MID

AF:

0.322

Gnomad NFE

AF:

0.425

Gnomad OTH

AF:

0.404

GnomAD3 exomes

AF:

0.469

AC:

36707

AN:

78206

Hom.:

8933

AF XY:

0.464

AC XY:

21128

AN XY:

45548

show subpopulations

Gnomad AFR exome

AF:

0.395

Gnomad AMR exome

AF:

0.585

Gnomad ASJ exome

AF:

0.388

Gnomad EAS exome

AF:

0.346

Gnomad SAS exome

AF:

0.456

Gnomad FIN exome

AF:

0.448

Gnomad NFE exome

AF:

0.462

Gnomad OTH exome

AF:

0.414

GnomAD4 exome

AF:

0.427

AC:

553283

AN:

1295012

Hom.:

119539

Cov.:

AF XY:

0.428

AC XY:

273242

AN XY:

638620

show subpopulations

Gnomad4 AFR exome

AF:

0.323

Gnomad4 AMR exome

AF:

0.558

Gnomad4 ASJ exome

AF:

0.386

Gnomad4 EAS exome

AF:

0.360

Gnomad4 SAS exome

AF:

0.444

Gnomad4 FIN exome

AF:

0.429

Gnomad4 NFE exome

AF:

0.429

Gnomad4 OTH exome

AF:

0.411

GnomAD4 genome

AF:

0.399

AC:

60566

AN:

151912

Hom.:

12365

Cov.:

AF XY:

0.403

AC XY:

29897

AN XY:

74250

show subpopulations

Gnomad4 AFR

AF:

0.332

Gnomad4 AMR

AF:

0.484

Gnomad4 ASJ

AF:

0.367

Gnomad4 EAS

AF:

0.278

Gnomad4 SAS

AF:

0.438

Gnomad4 FIN

AF:

0.435

Gnomad4 NFE

AF:

0.425

Gnomad4 OTH

AF:

0.406

Alfa

AF:

0.401

Hom.:

1556

Bravo

AF:

0.399

Asia WGS

AF:

0.319

AC:

1100

AN:

3448

ClinVar

Significance: Benign

Submissions summary: Benign:13

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

not specified

Benign:6

May 25, 2018

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Clinical Genetics, Academic Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Mucopolysaccharidosis type 1

Benign:4

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Jan 02, 2025

ClinGen Lysosomal Storage Disorder Variant Curation Expert Panel

Significance: Benign

Review Status: reviewed by expert panel

Collection Method: curation

The NM_000203.5:c.24C>A variant in IDUA is a synonymous (silent) variant (p.Ala8=). The Grpmax Filtering AF (95% confidence) in gnomAD v4.1.0 is 0.5236 in the Admixed American population. This 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: 92638). In summary, this variant meets the criteria to be classified as benign for mucopolysaccharidosis type 1. IDUA-specific 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 January 2, 2025) -

May 11, 2017

Natera, Inc.

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided

Benign:3

Jun 13, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Oct 23, 2015

Mayo Clinic Laboratories, Mayo Clinic

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.69

CADD

Benign

6.7

DANN

Benign

0.59

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over