rs74349352
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Variant summary
Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2
The NM_000374.5(UROD):c.*3G>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0112 in 1,614,194 control chromosomes in the GnomAD database, including 127 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Genomes: 𝑓 0.0087 ( 4 hom., cov: 32)
Exomes 𝑓: 0.011 ( 123 hom. )
Consequence
UROD
NM_000374.5 3_prime_UTR
NM_000374.5 3_prime_UTR
Scores
2
Clinical Significance
Conservation
PhyloP100: -1.01
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 Benign. Variant got -13 ACMG points.
BP4
?
Computational evidence support a benign effect (BayesDel_noAF=-0.85).
BP6
?
Variant 1-45015501-G-A is Benign according to our data. Variant chr1-45015501-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 255960.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, Likely_benign=2, Benign=1}.
BS1
?
Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00874 (1331/152310) while in subpopulation NFE AF= 0.0127 (865/68024). AF 95% confidence interval is 0.012. There are 4 homozygotes in gnomad4. There are 629 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
BS2
?
High Homozygotes in GnomAd4 at 4 SD gene
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
UROD | NM_000374.5 | c.*3G>A | 3_prime_UTR_variant | 10/10 | ENST00000246337.9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
UROD | ENST00000246337.9 | c.*3G>A | 3_prime_UTR_variant | 10/10 | 1 | NM_000374.5 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.00875 AC: 1331AN: 152192Hom.: 4 Cov.: 32
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GnomAD3 exomes AF: 0.00972 AC: 2445AN: 251470Hom.: 10 AF XY: 0.00978 AC XY: 1329AN XY: 135914
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GnomAD4 exome AF: 0.0115 AC: 16807AN: 1461884Hom.: 123 Cov.: 31 AF XY: 0.0113 AC XY: 8253AN XY: 727246
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GnomAD4 genome ? AF: 0.00874 AC: 1331AN: 152310Hom.: 4 Cov.: 32 AF XY: 0.00845 AC XY: 629AN XY: 74472
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:1Benign:3
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
not provided Uncertain:1Benign:1
Uncertain significance, criteria provided, single submitter | clinical testing | Mayo Clinic Laboratories, Mayo Clinic | Jun 12, 2023 | BS1, BP2 - |
Benign, criteria provided, single submitter | clinical testing | Invitae | Jan 20, 2024 | - - |
not specified Benign:1
Likely benign, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | - | - - |
Familial porphyria cutanea tarda Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Mar 06, 2018 | 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 likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. - |
Computational scores
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Name
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BayesDel_noAF
Benign
CADD
Benign
DANN
Benign
RBP_binding_hub_radar
RBP_regulation_power_radar
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at