1-45012895-C-G
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Variant summary
Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP3
The NM_000374.5(UROD):c.21-12C>G variant causes a splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000031 in 1,613,466 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).
Frequency
Genomes: 𝑓 0.000020 ( 0 hom., cov: 32)
Exomes 𝑓: 0.0000014 ( 0 hom. )
Consequence
UROD
NM_000374.5 splice_polypyrimidine_tract, intron
NM_000374.5 splice_polypyrimidine_tract, intron
Scores
2
Splicing: ADA: 0.9997
2
Clinical Significance
Conservation
PhyloP100: -0.765
Genes affected
UROD (HGNC:12591): (uroporphyrinogen decarboxylase) This gene encodes an enzyme in the heme biosynthetic pathway. This enzyme is responsible for catalyzing the conversion of uroporphyrinogen to coproporphyrinogen through the removal of four carboxymethyl side chains. Mutations and deficiency in this enzyme are known to cause familial porphyria cutanea tarda and hepatoerythropoetic porphyria.[provided by RefSeq, Aug 2010]
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ACMG classification
Classification made for transcript
Verdict is Uncertain_significance. Variant got 3 ACMG points.
PM2
Very rare variant in population databases, with high coverage;
PP3
Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF, max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
UROD | NM_000374.5 | c.21-12C>G | splice_polypyrimidine_tract_variant, intron_variant | ENST00000246337.9 | |||
UROD | NR_036510.2 | n.71C>G | non_coding_transcript_exon_variant | 2/10 | |||
UROD | NR_158184.1 | n.71C>G | non_coding_transcript_exon_variant | 2/10 | |||
UROD | NR_158185.1 | n.33-12C>G | splice_polypyrimidine_tract_variant, intron_variant, non_coding_transcript_variant |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
UROD | ENST00000246337.9 | c.21-12C>G | splice_polypyrimidine_tract_variant, intron_variant | 1 | NM_000374.5 | P1 |
Frequencies
GnomAD3 genomes AF: 0.0000197 AC: 3AN: 152144Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.00000799 AC: 2AN: 250416Hom.: 0 AF XY: 0.0000148 AC XY: 2AN XY: 135532
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GnomAD4 exome AF: 0.00000137 AC: 2AN: 1461322Hom.: 0 Cov.: 32 AF XY: 0.00000275 AC XY: 2AN XY: 726988
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GnomAD4 genome AF: 0.0000197 AC: 3AN: 152144Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1AN XY: 74310
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not provided Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Mayo Clinic Laboratories, Mayo Clinic | Aug 25, 2021 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | May 23, 2023 | This sequence change falls in intron 1 of the UROD gene. It does not directly change the encoded amino acid sequence of the UROD protein. This variant is present in population databases (rs775210041, gnomAD 0.002%). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. ClinVar contains an entry for this variant (Variation ID: 1693877). This variant has not been reported in the literature in individuals affected with UROD-related conditions. - |
Computational scores
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Name
Calibrated prediction
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BayesDel_noAF
Benign
CADD
Benign
DANN
Benign
Splicing
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dbscSNV1_ADA
Pathogenic
dbscSNV1_RF
Pathogenic
SpliceAI score (max)
Details are displayed if max score is > 0.2
DS_AG_spliceai
Position offset: 1
DS_AL_spliceai
Position offset: 12
Find out detailed SpliceAI scores and Pangolin per-transcript scores at