4-1002131-G-C

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.942G>C variant in IDUA is a synonymous (silent) variant (p.Ala314=). The Grpmax Filtering AF (95% confidence) in gnomAD v4.1.0 is 0.2937 in the South Asian 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: 92650). 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/CA145892/MONDO:0001586/091

Frequency

Genomes: 𝑓 0.17 ( 2352 hom., cov: 33)
Exomes 𝑓: 0.16 ( 19683 hom. )

Consequence

IDUA
NM_000203.5 synonymous

Scores

2

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:14

Conservation

PhyloP100: -4.78
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]

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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
IDUANM_000203.5 linkuse as main transcriptc.942G>C p.Ala314Ala synonymous_variant 7/14 ENST00000514224.2 NP_000194.2 P35475-1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
IDUAENST00000514224.2 linkuse as main transcriptc.942G>C p.Ala314Ala synonymous_variant 7/142 NM_000203.5 ENSP00000425081.2 P35475-1
IDUAENST00000247933.9 linkuse as main transcriptc.942G>C p.Ala314Ala synonymous_variant 7/141 ENSP00000247933.4 P35475-1
IDUAENST00000514698.5 linkuse as main transcriptn.942G>C non_coding_transcript_exon_variant 5/115
IDUAENST00000652070.1 linkuse as main transcriptn.998G>C non_coding_transcript_exon_variant 6/13

Frequencies

GnomAD3 genomes
AF:
0.172
AC:
26198
AN:
152082
Hom.:
2356
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.212
Gnomad AMI
AF:
0.171
Gnomad AMR
AF:
0.124
Gnomad ASJ
AF:
0.165
Gnomad EAS
AF:
0.200
Gnomad SAS
AF:
0.299
Gnomad FIN
AF:
0.143
Gnomad MID
AF:
0.234
Gnomad NFE
AF:
0.152
Gnomad OTH
AF:
0.182
GnomAD3 exomes
AF:
0.172
AC:
28962
AN:
168596
Hom.:
2858
AF XY:
0.181
AC XY:
16331
AN XY:
90280
show subpopulations
Gnomad AFR exome
AF:
0.215
Gnomad AMR exome
AF:
0.0809
Gnomad ASJ exome
AF:
0.161
Gnomad EAS exome
AF:
0.209
Gnomad SAS exome
AF:
0.297
Gnomad FIN exome
AF:
0.144
Gnomad NFE exome
AF:
0.157
Gnomad OTH exome
AF:
0.173
GnomAD4 exome
AF:
0.161
AC:
226832
AN:
1411856
Hom.:
19683
Cov.:
35
AF XY:
0.164
AC XY:
114702
AN XY:
697474
show subpopulations
Gnomad4 AFR exome
AF:
0.220
Gnomad4 AMR exome
AF:
0.0868
Gnomad4 ASJ exome
AF:
0.161
Gnomad4 EAS exome
AF:
0.168
Gnomad4 SAS exome
AF:
0.297
Gnomad4 FIN exome
AF:
0.151
Gnomad4 NFE exome
AF:
0.151
Gnomad4 OTH exome
AF:
0.168
GnomAD4 genome
AF:
0.172
AC:
26195
AN:
152200
Hom.:
2352
Cov.:
33
AF XY:
0.172
AC XY:
12811
AN XY:
74396
show subpopulations
Gnomad4 AFR
AF:
0.212
Gnomad4 AMR
AF:
0.123
Gnomad4 ASJ
AF:
0.165
Gnomad4 EAS
AF:
0.199
Gnomad4 SAS
AF:
0.299
Gnomad4 FIN
AF:
0.143
Gnomad4 NFE
AF:
0.152
Gnomad4 OTH
AF:
0.181
Alfa
AF:
0.153
Hom.:
625
Bravo
AF:
0.169
Asia WGS
AF:
0.249
AC:
871
AN:
3478

ClinVar

Significance: Benign
Submissions summary: Benign:14
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not specified Benign:5
Benign, no assertion criteria providedclinical testingClinical Genetics, Academic Medical Center-- -
Benign, no assertion criteria providedclinical testingDiagnostic Laboratory, Department of Genetics, University Medical Center Groningen-- -
Benign, criteria provided, single submitterclinical testingEurofins Ntd Llc (ga)Dec 11, 2015- -
Benign, criteria provided, single submitterclinical testingPreventionGenetics, part of Exact Sciences-- -
Benign, no assertion criteria providedclinical testingClinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center-- -
Mucopolysaccharidosis type 1 Benign:3
Benign, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpFeb 01, 2024- -
Benign, no assertion criteria providedclinical testingNatera, Inc.May 11, 2017- -
Benign, criteria provided, single submitterclinical testingIllumina Laboratory Services, IlluminaJan 13, 2018This 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. -
not provided Benign:3
Benign, criteria provided, single submitternot providedBreakthrough Genomics, Breakthrough Genomics-- -
Benign, no assertion criteria providedclinical testingMayo Clinic Laboratories, Mayo ClinicFeb 02, 2016- -
Benign, criteria provided, single submitterclinical testingGeneDxJul 05, 2018- -
Mucopolysaccharidosis, MPS-I-H/S Benign:1
Benign, criteria provided, single submitterclinical testingGenome-Nilou LabJul 10, 2021- -
Mucopolysaccharidosis, MPS-I-S Benign:1
Benign, criteria provided, single submitterclinical testingGenome-Nilou LabJul 10, 2021- -
Hurler syndrome Benign:1
Benign, criteria provided, single submitterclinical testingGenome-Nilou LabJul 10, 2021- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
-0.91
CADD
Benign
0.54
DANN
Benign
0.29
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7

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.

Other links and lift over

dbSNP: rs6830825; hg19: chr4-995919; COSMIC: COSV56102732; COSMIC: COSV56102732; API