chr4-1002338-AACG-A
Variant summary
Our verdict is Pathogenic. Variant got 13 ACMG points: 13P and 0B. PM1PM2PM4_SupportingPP5_Very_Strong
The NM_000203.5(IDUA):c.1045_1047delGAC(p.Asp349del) variant causes a conservative inframe deletion change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000372 in 1,613,082 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★).
Frequency
Consequence
NM_000203.5 conservative_inframe_deletion
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 13 ACMG points.
Transcripts
RefSeq
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
IDUA | ENST00000514224.2 | c.1045_1047delGAC | p.Asp349del | conservative_inframe_deletion | Exon 8 of 14 | 2 | NM_000203.5 | ENSP00000425081.2 | ||
IDUA | ENST00000247933.9 | c.1045_1047delGAC | p.Asp349del | conservative_inframe_deletion | Exon 8 of 14 | 1 | ENSP00000247933.4 | |||
IDUA | ENST00000514698.5 | n.1152_1154delGAC | non_coding_transcript_exon_variant | Exon 5 of 11 | 5 | |||||
IDUA | ENST00000652070.1 | n.1101_1103delGAC | non_coding_transcript_exon_variant | Exon 7 of 13 |
Frequencies
GnomAD3 genomes AF: 0.00000657 AC: 1AN: 152220Hom.: 0 Cov.: 34
GnomAD4 exome AF: 0.00000342 AC: 5AN: 1460862Hom.: 0 AF XY: 0.00000413 AC XY: 3AN XY: 726730
GnomAD4 genome AF: 0.00000657 AC: 1AN: 152220Hom.: 0 Cov.: 34 AF XY: 0.0000134 AC XY: 1AN XY: 74372
ClinVar
Submissions by phenotype
Hurler syndrome Pathogenic:2
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Mucopolysaccharidosis type 1 Pathogenic:1
This variant, c.1045_1047del, results in the deletion of 1 amino acid(s) of the IDUA protein (p.Asp349del), but otherwise preserves the integrity of the reading frame. This variant is present in population databases (no rsID available, gnomAD 0.06%). This variant has been observed in individuals with mucopolysaccharidosis type I (PMID: 21394825, 27392569). ClinVar contains an entry for this variant (Variation ID: 557885). This variant disrupts a region of the IDUA protein in which other variant(s) (p.Asp349Tyr) have been determined to be pathogenic (PMID: 12203999, 12559846, 28752568, 30809705). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. -
not provided Pathogenic:1
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Mucopolysaccharidosis, MPS-I-S;C0086431:Mucopolysaccharidosis, MPS-I-H/S;C0086795:Hurler syndrome Pathogenic:1
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Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at