rs58037052

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 4P and 20B. PM1PM5BP4_StrongBP6_Very_StrongBS1BS2

The NM_000203.5(IDUA):c.235G>A(p.Ala79Thr) variant causes a missense change. The variant allele was found at a frequency of 0.00158 in 1,611,212 control chromosomes in the GnomAD database, including 30 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign,other (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A79V) has been classified as Likely pathogenic.

Frequency

Genomes: 𝑓 0.0085 ( 15 hom., cov: 33)

Exomes 𝑓: 0.00087 ( 15 hom. )

Consequence

IDUA
NM_000203.5 missense

Scores

Clinical Significance

Benign/Likely benign; other criteria provided, multiple submitters, no conflicts U:1B:9O:3

Conservation

PhyloP100: 4.29

Publications

21 publications found

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 Gene-Disease associations (from GenCC):

nephrolithiasis susceptibility caused by SLC26A1
Inheritance: AR Classification: MODERATE, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics

SLC26A1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -16 ACMG points.

PM1

In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 12 uncertain in NM_000203.5

PM5

Other missense variant is known to change same aminoacid residue: Variant chr4-987886-C-T is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 1458769.Status of the report is reviewed_by_expert_panel, 3 stars.

BP4

Computational evidence support a benign effect (MetaRNN=0.0113580525).

BP6

Variant 4-987885-G-A is Benign according to our data. Variant chr4-987885-G-A is described in ClinVar as Benign/Likely_benign|other. ClinVar VariationId is 195038.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00846 (1289/152316) while in subpopulation AFR AF = 0.0299 (1242/41562). AF 95% confidence interval is 0.0285. There are 15 homozygotes in GnomAd4. There are 620 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 15 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
IDUA	NM_000203.5 link	c.235G>A	p.Ala79Thr	missense_variant	Exon 2 of 14	ENST00000514224.2	NP_000194.2	P35475-1
SLC26A1	NM_022042.4 link	c.*948C>T		3_prime_UTR_variant	Exon 3 of 3	ENST00000398516.3	NP_071325.2	Q9H2B4-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
IDUA	ENST00000514224.2 link	c.235G>A	p.Ala79Thr	missense_variant	Exon 2 of 14	2	NM_000203.5	ENSP00000425081.2		P35475-1
SLC26A1	ENST00000398516.3 link	c.*948C>T		3_prime_UTR_variant	Exon 3 of 3	1	NM_022042.4	ENSP00000381528.2		Q9H2B4-1

Frequencies

GnomAD3 genomes

AF:

0.00848

AC:

1291

AN:

152198

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0300

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00229

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000882

Gnomad OTH

AF:

0.00287

GnomAD2 exomes

AF:

0.00239

AC:

572

AN:

239166

AF XY:

0.00173

show subpopulations

Gnomad AFR exome

AF:

0.0325

Gnomad AMR exome

AF:

0.00164

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000856

Gnomad OTH exome

AF:

0.000850

GnomAD4 exome

AF:

0.000866

AC:

1263

AN:

1458896

Hom.:

Cov.:

AF XY:

0.000733

AC XY:

532

AN XY:

725620

show subpopulations

African (AFR)

AF:

0.0314

AC:

1050

AN:

33440

American (AMR)

AF:

0.00146

AC:

AN:

44532

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26088

East Asian (EAS)

AF:

0.0000252

AC:

AN:

39642

South Asian (SAS)

AF:

0.0000931

AC:

AN:

85952

European-Finnish (FIN)

AF:

0.00

AC:

AN:

51828

Middle Eastern (MID)

AF:

0.00139

AC:

AN:

5746

European-Non Finnish (NFE)

AF:

0.0000288

AC:

AN:

1111380

Other (OTH)

AF:

0.00164

AC:

AN:

60288

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.466

Heterozygous variant carriers

170

254

339

424

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

128

160

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00846

AC:

1289

AN:

152316

Hom.:

Cov.:

AF XY:

0.00832

AC XY:

620

AN XY:

74490

show subpopulations

African (AFR)

AF:

0.0299

AC:

1242

AN:

41562

American (AMR)

AF:

0.00229

AC:

AN:

15306

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5182

South Asian (SAS)

AF:

0.00

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10624

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0000882

AC:

AN:

68022

Other (OTH)

AF:

0.00284

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

130

195

260

325

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00275

Hom.:

Bravo

AF:

0.00964

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.000259

AC:

ESP6500AA

AF:

0.0285

AC:

125

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.00285

AC:

344

Asia WGS

AF:

0.00144

AC:

AN:

3478

ClinVar

Significance: Benign/Likely benign; other

Submissions summary: Uncertain:1Benign:9Other:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Uncertain:1Benign:4Other:1

Jul 27, 2016

Mayo Clinic Laboratories, Mayo Clinic

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

May 25, 2018

Eurofins Ntd Llc (ga)

Significance:other

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- Variant classified as "other reportable" ??? variant is clinically benign (not associated with disease) but is reported when observed (e.g. pseudodeficiency alleles).

Jan 27, 2017

Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Sep 18, 2018

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is associated with the following publications: (PMID: 27939258) -

Mucopolysaccharidosis type 1

Benign:1Other:2

GeneReviews

Significance:not provided

Review Status:no classification provided

Collection Method:literature only

Pseudodeficiency variants -

Apr 28, 2017

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases was too high to be consistent with this variant causing disease. Therefore, this variant is classified as benign. -

Dec 26, 2018

Labcorp Genetics (formerly Invitae), Labcorp

Significance:other

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- pseudodeficiency allele

not specified

Benign:2

Clinical Genetics, Academic Medical Center

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Nov 01, 2021

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant summary: IDUA c.235G>A (p.Ala79Thr) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.0031 in 270526 control chromosomes, predominantly at a frequency of 0.031 within the African or African-American subpopulation in the gnomAD database, including 9 homozygotes. The observed variant frequency within African or African-American control individuals in the gnomAD database is approximately 12 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 a benign polymorphism found primarily in populations of African or African-American origin. The variant, c.235G>A, also has been reported in the literature as a well-known pseudodeficiency allele, prevalent in the African American subpopulation. Individuals with pseudodeficiency allele(s) exhibit decreased alpha-L-iduronidase enzyme activity in biochemical assays using artificial substrates, but otherwise show no evidence of disease (see e.g. in Clarke_2016). Seven ClinVar submitters (evaluation after 2014) cite the variant as benign/likely benign pseudodeficiency allele (n=6) or VUS (n=1). Based on the evidence outlined above, the variant was classified as benign. -

Hurler syndrome

Benign:1

May 16, 2018

Counsyl

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

This submission and the accompanying classification are no longer maintained by the submitter. For more information on current observations and classification, please contact variantquestions@myriad.com. -

Calcium oxalate urolithiasis

Benign:1

Jul 19, 2021

Fulgent Genetics, Fulgent Genetics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.31

BayesDel_addAF

Benign

-0.20

BayesDel_noAF

Uncertain

-0.040

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.74

Eigen

Benign

0.087

Eigen_PC

Benign

0.026

FATHMM_MKL

Benign

0.52

LIST_S2

Uncertain

0.90

MetaRNN

Benign

0.011

MetaSVM

Benign

-0.85

MutationAssessor

Uncertain

2.5

PhyloP100

4.3

PrimateAI

Benign

0.41

PROVEAN

Benign

-0.84

REVEL

Uncertain

0.53

Sift

Uncertain

0.013

Sift4G

Uncertain

0.018

Polyphen

0.99

Vest4

0.75

MVP

0.98

MPC

0.74

ClinPred

0.023

GERP RS

2.5

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.20

gMVP

0.84

Mutation Taster

=94/6

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over