rs121918062
Variant summary
Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM2PP3_StrongPP5_Very_Strong
The NM_000374.5(UROD):c.942G>A(p.Glu314=) variant causes a splice region, synonymous change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,461,260 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★★).
Frequency
Consequence
NM_000374.5 splice_region, synonymous
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 14 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
UROD | NM_000374.5 | c.942G>A | p.Glu314= | splice_region_variant, synonymous_variant | 9/10 | ENST00000246337.9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
UROD | ENST00000246337.9 | c.942G>A | p.Glu314= | splice_region_variant, synonymous_variant | 9/10 | 1 | NM_000374.5 | P1 |
Frequencies
GnomAD3 genomes ? Cov.: 33
GnomAD3 exomes AF: 0.00000398 AC: 1AN: 251172Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 135764
GnomAD4 exome AF: 0.00000205 AC: 3AN: 1461260Hom.: 0 Cov.: 34 AF XY: 0.00 AC XY: 0AN XY: 726930
GnomAD4 genome ? Cov.: 33
ClinVar
Submissions by phenotype
UROD-related disorder Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Jun 07, 2023 | The UROD c.942G>A variant is not predicted to result in an amino acid change (p.=). This variant was reported in an individual with familial porphyria cutanea tarda and functional studies showed the c.942G>A variant results in aberrant splicing through exon 9 skipping (Mendez et al 1998. PubMed ID: 9792863). This variant is reported in 0.00088% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/1-45480678-G-A). This variant is interpreted as likely pathogenic. - |
not provided Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Invitae | Nov 19, 2023 | This sequence change affects codon 314 of the UROD mRNA. It is a 'silent' change, meaning that it does not change the encoded amino acid sequence of the UROD protein. RNA analysis indicates that this variant induces altered splicing and likely disrupts the C-terminus of the protein. This variant is present in population databases (rs121918062, gnomAD 0.0009%). This variant has been observed in individual(s) with porphyria cutanea tarda (PMID: 9792863). ClinVar contains an entry for this variant (Variation ID: 72). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Studies have shown that this variant results in exon 9 skipping and introduces a new termination codon (PMID: 9792863). However the mRNA is not expected to undergo nonsense-mediated decay. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. - |
Familial porphyria cutanea tarda Pathogenic:1
Pathogenic, no assertion criteria provided | literature only | OMIM | Nov 01, 1998 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at