rs121908015
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Variant summary
Our verdict is Pathogenic. Variant got 13 ACMG points: 13P and 0B. PM1PM2PP3PP5_Very_Strong
The NM_000375.3(UROS):c.10C>T(p.Leu4Phe) variant causes a missense change. The variant allele was found at a frequency of 0.00000991 in 1,614,044 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 0.000033 ( 0 hom., cov: 32)
Exomes 𝑓: 0.0000075 ( 0 hom. )
Consequence
UROS
NM_000375.3 missense
NM_000375.3 missense
Scores
7
10
1
Clinical Significance
Conservation
PhyloP100: 4.33
Genes affected
UROS (HGNC:12592): (uroporphyrinogen III synthase) The protein encoded by this gene catalyzes the fourth step of porphyrin biosynthesis in the heme biosynthetic pathway. Defects in this gene cause congenital erythropoietic porphyria (Gunther's disease). [provided by RefSeq, Jul 2008]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 13 ACMG points.
PM1
?
In a chain Uroporphyrinogen-III synthase (size 264) in uniprot entity HEM4_HUMAN there are 25 pathogenic changes around while only 9 benign (74%) in NM_000375.3
PM2
?
Very rare variant in population databases, with high coverage;
PP3
?
MetaRNN computational evidence supports a deleterious effect, 0.829
PP5
?
Variant 10-125816490-G-A is Pathogenic according to our data. Variant chr10-125816490-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 3755.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
UROS | NM_000375.3 | c.10C>T | p.Leu4Phe | missense_variant | 2/10 | ENST00000368797.10 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
UROS | ENST00000368797.10 | c.10C>T | p.Leu4Phe | missense_variant | 2/10 | 1 | NM_000375.3 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.0000329 AC: 5AN: 152154Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.0000239 AC: 6AN: 251476Hom.: 0 AF XY: 0.0000221 AC XY: 3AN XY: 135912
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GnomAD4 exome AF: 0.00000752 AC: 11AN: 1461890Hom.: 0 Cov.: 31 AF XY: 0.00000825 AC XY: 6AN XY: 727248
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GnomAD4 genome ? AF: 0.0000329 AC: 5AN: 152154Hom.: 0 Cov.: 32 AF XY: 0.0000404 AC XY: 3AN XY: 74312
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ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:3
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Cutaneous porphyria Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Jun 26, 2023 | Variant summary: UROS c.10C>T (p.Leu4Phe) results in a non-conservative amino acid change located in the Tetrapyrrole biosynthesis, uroporphyrinogen III synthase domain (IPR003754) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 2.4e-05 in 251476 control chromosomes (gnomAD). c.10C>T has been reported in the literature in multiple bi-allelic individuals affected with Cutaneous Porphyria (examples: Boulechfar_1992, Xu_1995, Katugampola_2012, and Ciftci_2018). These data indicate that the variant is very likely to be associated with disease. Multiple publications have reported experimental evidence that this variant reduces normal activity of the protein (examples: Fortian_2009, and Boulechfar_1992). The following publications have been ascertained in the context of this evaluation (PMID: 1733834, 7860775 , 30706587, 22816431, 19099412). One submitter has cited clinical-significance assessments for this variant to ClinVar after 2014 and has classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. - |
Pathogenic, no assertion criteria provided | literature only | OMIM | Jan 01, 1992 | - - |
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Aug 13, 2021 | This sequence change replaces leucine with phenylalanine at codon 4 of the UROS protein (p.Leu4Phe). The leucine residue is highly conserved and there is a small physicochemical difference between leucine and phenylalanine. For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this variant affects UROS protein function (PMID: 1733834, 19099412). This variant has been observed in individual(s) with congenital erythropoietic porphyria (PMID: 1733834, 30706587, 7860775). ClinVar contains an entry for this variant (Variation ID: 3755). This variant is present in population databases (rs121908015, ExAC 0.004%). - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Uncertain
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Uncertain
DEOGEN2
Uncertain
D;D;D;.;.;T;T;T
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Uncertain
D
M_CAP
Uncertain
D
MetaRNN
Pathogenic
D;D;D;D;D;D;D;D
MetaSVM
Pathogenic
D
MutationAssessor
Uncertain
M;M;M;.;.;.;.;.
MutationTaster
Benign
A;A;A;A
PrimateAI
Uncertain
T
PROVEAN
Uncertain
D;.;D;.;.;N;D;D
REVEL
Pathogenic
Sift
Uncertain
D;.;D;.;.;D;D;D
Sift4G
Uncertain
D;.;D;.;.;.;D;D
Polyphen
D;D;D;.;.;.;.;.
Vest4
MVP
MPC
ClinPred
D
GERP RS
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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