4-1002460-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.1164G>C (p.Thr388=) variant is a synonymous (silent) variant. The highest population minor allele frequency in gnomAD v4.1.0 is 0.2976 (25114/84382 alleles; 3978 homozygotes; Grpmax Filtering AF 95% confidence = 0.2945) in the South Asian population, which 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: 92625). In summary, this variant meets the criteria to be classified as benign for MPS I based on the 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/CA145867/MONDO:0001586/091

Frequency

Genomes: 𝑓 0.17 ( 2368 hom., cov: 34)
Exomes 𝑓: 0.16 ( 19662 hom. )

Consequence

IDUA
NM_000203.5 synonymous

Scores

2

Clinical Significance

Benign reviewed by expert panel B:13

Conservation

PhyloP100: -6.27
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 rank MANE Protein UniProt
IDUANM_000203.5 linkc.1164G>C p.Thr388Thr synonymous_variant Exon 8 of 14 ENST00000514224.2 NP_000194.2 P35475-1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
IDUAENST00000514224.2 linkc.1164G>C p.Thr388Thr synonymous_variant Exon 8 of 14 2 NM_000203.5 ENSP00000425081.2 P35475-1
IDUAENST00000247933.9 linkc.1164G>C p.Thr388Thr synonymous_variant Exon 8 of 14 1 ENSP00000247933.4 P35475-1
IDUAENST00000514698.5 linkn.1271G>C non_coding_transcript_exon_variant Exon 5 of 11 5
IDUAENST00000652070.1 linkn.1220G>C non_coding_transcript_exon_variant Exon 7 of 13

Frequencies

GnomAD3 genomes
AF:
0.173
AC:
26241
AN:
152064
Hom.:
2372
Cov.:
34
show subpopulations
Gnomad AFR
AF:
0.213
Gnomad AMI
AF:
0.171
Gnomad AMR
AF:
0.123
Gnomad ASJ
AF:
0.166
Gnomad EAS
AF:
0.201
Gnomad SAS
AF:
0.300
Gnomad FIN
AF:
0.144
Gnomad MID
AF:
0.236
Gnomad NFE
AF:
0.152
Gnomad OTH
AF:
0.182
GnomAD3 exomes
AF:
0.174
AC:
26448
AN:
151750
Hom.:
2720
AF XY:
0.185
AC XY:
15043
AN XY:
81426
show subpopulations
Gnomad AFR exome
AF:
0.218
Gnomad AMR exome
AF:
0.0822
Gnomad ASJ exome
AF:
0.162
Gnomad EAS exome
AF:
0.215
Gnomad SAS exome
AF:
0.300
Gnomad FIN exome
AF:
0.144
Gnomad NFE exome
AF:
0.160
Gnomad OTH exome
AF:
0.176
GnomAD4 exome
AF:
0.161
AC:
225509
AN:
1398620
Hom.:
19662
Cov.:
35
AF XY:
0.165
AC XY:
113950
AN XY:
690122
show subpopulations
Gnomad4 AFR exome
AF:
0.222
Gnomad4 AMR exome
AF:
0.0884
Gnomad4 ASJ exome
AF:
0.161
Gnomad4 EAS exome
AF:
0.168
Gnomad4 SAS exome
AF:
0.297
Gnomad4 FIN exome
AF:
0.152
Gnomad4 NFE exome
AF:
0.151
Gnomad4 OTH exome
AF:
0.169
GnomAD4 genome
AF:
0.172
AC:
26238
AN:
152180
Hom.:
2368
Cov.:
34
AF XY:
0.173
AC XY:
12844
AN XY:
74382
show subpopulations
Gnomad4 AFR
AF:
0.212
Gnomad4 AMR
AF:
0.123
Gnomad4 ASJ
AF:
0.166
Gnomad4 EAS
AF:
0.201
Gnomad4 SAS
AF:
0.300
Gnomad4 FIN
AF:
0.144
Gnomad4 NFE
AF:
0.152
Gnomad4 OTH
AF:
0.181
Alfa
AF:
0.122
Hom.:
452
Bravo
AF:
0.170
Asia WGS
AF:
0.248
AC:
866
AN:
3474

ClinVar

Significance: Benign
Submissions summary: Benign:13
Revision: reviewed by expert panel
LINK: link

Submissions by phenotype

not specified Benign:5
-
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

- -

Nov 02, 2017
Eurofins Ntd Llc (ga)
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Mucopolysaccharidosis type 1 Benign:4
Dec 06, 2024
ClinGen Lysosomal Storage Disorder Variant Curation Expert Panel
Significance: Benign
Review Status: reviewed by expert panel
Collection Method: curation

The NM_000203.5: c.1164G>C (p.Thr388=) variant is a synonymous (silent) variant. The highest population minor allele frequency in gnomAD v4.1.0 is 0.2976 (25114/84382 alleles; 3978 homozygotes; Grpmax Filtering AF 95% confidence = 0.2945) in the South Asian population, which 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: 92625). In summary, this variant meets the criteria to be classified as benign for MPS I based on the 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) -

Feb 04, 2025
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Jan 13, 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. -

Aug 08, 2017
Natera, Inc.
Significance: Benign
Review Status: no assertion criteria provided
Collection Method: clinical testing

- -

not provided Benign:4
Aug 29, 2018
GeneDx
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 16438163, 28649516, 9391892, 12509712) -

-
Breakthrough Genomics, Breakthrough Genomics
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: not provided

- -

Feb 02, 2016
Mayo Clinic Laboratories, Mayo Clinic
Significance: Benign
Review Status: no assertion criteria provided
Collection Method: clinical testing

- -

Jan 15, 2016
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
-0.90
CADD
Benign
0.017
DANN
Benign
0.63

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.020
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: rs6836258; hg19: chr4-996248; COSMIC: COSV56104304; COSMIC: COSV56104304; API