4-987144-G-A

Position:

chr4-987144-G-A

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.60G>A variant in IDUA is a synonymous (silent) variant (p.Ala20=). The highest population minor allele frequency in gnomAD v4.1.0 is 0.5266 (17787/33780 alleles; 4836 homozygotes; Grpmax Filtering AF 95% confidence = 0.5201) in the Admixed American population, which is higher than the ClinGen Lysosomal Diseases VCEP’s threshold for BA1 (>0.005), and therefore meets this criterion (BA1). 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 December 6, 2024) LINK:https://erepo.genome.network/evrepo/ui/classification/CA145888/MONDO:0001586/091

Frequency

Genomes: 𝑓 0.40 ( 12417 hom., cov: 35)

Exomes 𝑓: 0.43 ( 117600 hom. )

Consequence

IDUA
NM_000203.5 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:13

Conservation

PhyloP100: -0.0380

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:

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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/exons	MANE	Protein	UniProt
IDUA	NM_000203.5 linkuse as main transcript	c.60G>A	p.Ala20=	synonymous_variant	1/14	ENST00000514224.2	NP_000194.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
IDUA	ENST00000514224.2 linkuse as main transcript	c.60G>A	p.Ala20=	synonymous_variant	1/14	2	NM_000203.5	ENSP00000425081	P1	P35475-1

Frequencies

GnomAD3 genomes

AF:

0.400

AC:

60646

AN:

151784

Hom.:

12409

Cov.:

show subpopulations

Gnomad AFR

AF:

0.329

Gnomad AMI

AF:

0.259

Gnomad AMR

AF:

0.483

Gnomad ASJ

AF:

0.367

Gnomad EAS

AF:

0.269

Gnomad SAS

AF:

0.439

Gnomad FIN

AF:

0.437

Gnomad MID

AF:

0.325

Gnomad NFE

AF:

0.429

Gnomad OTH

AF:

0.409

GnomAD3 exomes

AF:

0.502

AC:

23733

AN:

47278

Hom.:

6014

AF XY:

0.496

AC XY:

13983

AN XY:

28186

show subpopulations

Gnomad AFR exome

AF:

0.371

Gnomad AMR exome

AF:

0.620

Gnomad ASJ exome

AF:

0.438

Gnomad EAS exome

AF:

0.387

Gnomad SAS exome

AF:

0.513

Gnomad FIN exome

AF:

0.465

Gnomad NFE exome

AF:

0.476

Gnomad OTH exome

AF:

0.456

GnomAD4 exome

AF:

0.431

AC:

540712

AN:

1255548

Hom.:

117600

Cov.:

AF XY:

0.432

AC XY:

266189

AN XY:

616424

show subpopulations

Gnomad4 AFR exome

AF:

0.321

Gnomad4 AMR exome

AF:

0.563

Gnomad4 ASJ exome

AF:

0.395

Gnomad4 EAS exome

AF:

0.342

Gnomad4 SAS exome

AF:

0.466

Gnomad4 FIN exome

AF:

0.436

Gnomad4 NFE exome

AF:

0.433

Gnomad4 OTH exome

AF:

0.415

GnomAD4 genome

AF:

0.399

AC:

60676

AN:

151892

Hom.:

12417

Cov.:

AF XY:

0.403

AC XY:

29934

AN XY:

74248

show subpopulations

Gnomad4 AFR

AF:

0.329

Gnomad4 AMR

AF:

0.482

Gnomad4 ASJ

AF:

0.367

Gnomad4 EAS

AF:

0.269

Gnomad4 SAS

AF:

0.439

Gnomad4 FIN

AF:

0.437

Gnomad4 NFE

AF:

0.429

Gnomad4 OTH

AF:

0.411

Alfa

AF:

0.190

Hom.:

357

Bravo

AF:

0.400

Asia WGS

AF:

0.308

AC:

1060

AN:

3444

ClinVar

Significance: Benign

Submissions summary: Benign:13

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:6

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	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	May 25, 2018	- -

not provided

Benign:4

Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Oct 23, 2015	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 13, 2018	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. -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Mucopolysaccharidosis type 1

Benign:3

Benign, no assertion criteria provided	clinical testing	Natera, Inc.	May 11, 2017	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.77

CADD

Benign

DANN

Benign

0.86

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