chr1-45012268-G-A
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Variant summary
Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1PM2PP5_Moderate
The NM_000374.5(UROD):c.3G>A(p.Met1?) variant causes a start lost change. The variant allele was found at a frequency of 0.00000657 in 152,158 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★).
Frequency
Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)
Consequence
UROD
NM_000374.5 start_lost
NM_000374.5 start_lost
Scores
8
4
4
Clinical Significance
Conservation
PhyloP100: 4.24
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 Pathogenic. Variant got 12 ACMG points.
PVS1
Start lost variant, no new inframe start found.
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 1-45012268-G-A is Pathogenic according to our data. Variant chr1-45012268-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 2733885.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr1-45012268-G-A is described in Lovd as [Pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
UROD | NM_000374.5 | c.3G>A | p.Met1? | start_lost | 1/10 | ENST00000246337.9 | |
UROD | NR_036510.2 | n.15G>A | non_coding_transcript_exon_variant | 1/10 | |||
UROD | NR_158184.1 | n.15G>A | non_coding_transcript_exon_variant | 1/10 | |||
UROD | NR_158185.1 | n.15G>A | non_coding_transcript_exon_variant | 1/10 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
UROD | ENST00000246337.9 | c.3G>A | p.Met1? | start_lost | 1/10 | 1 | NM_000374.5 | P1 |
Frequencies
GnomAD3 genomes AF: 0.00000657 AC: 1AN: 152158Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.00000398 AC: 1AN: 251488Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 135918
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GnomAD4 exome Cov.: 31
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GnomAD4 genome AF: 0.00000657 AC: 1AN: 152158Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 74330
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ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:1
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Dec 20, 2022 | For these reasons, this variant has been classified as Pathogenic. This variant disrupts a region of the UROD protein in which other variant(s) (p.Trp34Arg) have been determined to be pathogenic (PMID: 19233912). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. Disruption of the initiator codon has been observed in individual(s) with porphyria cutanea tarda (PMID: 19419417). This variant is present in population databases (rs368362264, gnomAD 0.0009%). This sequence change affects the initiator methionine of the UROD mRNA. The next in-frame methionine is located at codon 36. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Uncertain
DEOGEN2
Benign
T;T;T;T
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Pathogenic
D
LIST_S2
Uncertain
D;D;D;.
M_CAP
Pathogenic
D
MetaRNN
Pathogenic
D;D;D;D
MetaSVM
Pathogenic
D
MutationTaster
Benign
D
PROVEAN
Benign
N;.;.;N
REVEL
Pathogenic
Sift
Pathogenic
D;.;.;D
Sift4G
Benign
T;.;.;D
Polyphen
P;.;.;.
Vest4
MutPred
Gain of catalytic residue at M1 (P = 0.0492);Gain of catalytic residue at M1 (P = 0.0492);Gain of catalytic residue at M1 (P = 0.0492);Gain of catalytic residue at M1 (P = 0.0492);
MVP
ClinPred
D
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
Varity_R
gMVP
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