chr4-987087-G-A
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Variant summary
Our verdict is Pathogenic. Variant got 20 ACMG points: 20P and 0B. PVS1PS1_ModeratePM2PP5_Very_Strong
The NM_000203.5(IDUA):c.3G>A(p.Met1?) variant causes a start lost change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).
Frequency
Genomes: not found (cov: 33)
Exomes 𝑓: 0.0000015 ( 0 hom. )
Failed GnomAD Quality Control
Consequence
IDUA
NM_000203.5 start_lost
NM_000203.5 start_lost
Scores
4
5
7
Clinical Significance
Conservation
PhyloP100: -0.193
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]
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]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 20 ACMG points.
PVS1
Start lost variant, no new inframe start found.
PS1
Another start lost variant in NM_000203.5 (IDUA) was described as [Pathogenic] in ClinVar as 550458
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 4-987087-G-A is Pathogenic according to our data. Variant chr4-987087-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 557150.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
IDUA | NM_000203.5 | c.3G>A | p.Met1? | start_lost | 1/14 | ENST00000514224.2 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
IDUA | ENST00000514224.2 | c.3G>A | p.Met1? | start_lost | 1/14 | 2 | NM_000203.5 | P1 |
Frequencies
GnomAD3 genomes Cov.: 33
GnomAD3 genomes
Cov.:
33
GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00000151 AC: 2AN: 1327324Hom.: 0 Cov.: 30 AF XY: 0.00000305 AC XY: 2AN XY: 656658
GnomAD4 exome
Data not reliable, filtered out with message: AS_VQSR
AF:
AC:
2
AN:
1327324
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Cov.:
30
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AC XY:
2
AN XY:
656658
Gnomad4 AFR exome
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GnomAD4 genome Cov.: 33
GnomAD4 genome
Cov.:
33
ClinVar
Significance: Likely pathogenic
Submissions summary: Pathogenic:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Mucopolysaccharidosis type 1 Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Jul 28, 2023 | Variant summary: IDUA c.3G>A (p.Met1Ile) alters the initiation codon and is predicted to result either in absence of the protein or truncation of the encoded protein due to translation initiation at a downstream codon (M133). Two of three in-silico tools predict a benign effect of the variant on protein function. The variant was absent in 106268 control chromosomes. c.3G>A has been reported in the literature in compound heterozygosity with a nonsense variant (Tyr343*) in one individual affected with Mucopolysaccharidosis Type 1 (Lee-Chen_1997). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Other variants upstream of the nearest downstream initiation codon (M133) have been classified as pathogenic by our laboratory. The following publication has been ascertained in the context of this evaluation (PMID: 9391892). One submitter has cited clinical-significance assessments for this variant to ClinVar after 2014 and has classified the variant as likely pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic. - |
Hurler syndrome Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Counsyl | Mar 05, 2018 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Uncertain
CADD
Benign
DANN
Benign
DEOGEN2
Benign
T;.
Eigen
Benign
Eigen_PC
Benign
FATHMM_MKL
Benign
N
LIST_S2
Uncertain
D;D
M_CAP
Pathogenic
D
MetaRNN
Pathogenic
D;D
MetaSVM
Uncertain
D
MutationTaster
Benign
D;D;N
PROVEAN
Benign
N;N
REVEL
Uncertain
Sift
Pathogenic
D;D
Sift4G
Uncertain
D;D
Polyphen
B;.
Vest4
MutPred
Loss of glycosylation at P6 (P = 0.0238);Loss of glycosylation at P6 (P = 0.0238);
MVP
ClinPred
D
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
Varity_R
gMVP
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at