rs121908014
Variant summary
Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PM1PM2PP3_StrongPP5
The NM_000375.3(UROS):c.683C>T(p.Thr228Met) variant causes a missense change. The variant allele was found at a frequency of 0.0000285 in 1,612,774 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 Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. T228T) has been classified as Likely benign.
Frequency
Consequence
NM_000375.3 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_pathogenic. Variant got 9 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
UROS | NM_000375.3 | c.683C>T | p.Thr228Met | missense_variant | 10/10 | ENST00000368797.10 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
UROS | ENST00000368797.10 | c.683C>T | p.Thr228Met | missense_variant | 10/10 | 1 | NM_000375.3 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.0000328 AC: 5AN: 152238Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.0000162 AC: 4AN: 246592Hom.: 0 AF XY: 0.0000149 AC XY: 2AN XY: 134200
GnomAD4 exome AF: 0.0000281 AC: 41AN: 1460536Hom.: 0 Cov.: 30 AF XY: 0.0000275 AC XY: 20AN XY: 726536
GnomAD4 genome ? AF: 0.0000328 AC: 5AN: 152238Hom.: 0 Cov.: 33 AF XY: 0.0000269 AC XY: 2AN XY: 74374
ClinVar
Submissions by phenotype
Cutaneous porphyria Pathogenic:1Uncertain:1
Pathogenic, no assertion criteria provided | literature only | OMIM | Jan 01, 1992 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Sep 07, 2022 | - - |
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Aug 27, 2021 | This sequence change replaces threonine with methionine at codon 228 of the UROS protein (p.Thr228Met). The threonine residue is highly conserved and there is a moderate physicochemical difference between threonine and methionine. This variant is present in population databases (rs121908014, ExAC 0.02%). This missense change has been observed in individual(s) with congenital erythropoietic porphyria (PMID: 1737856, 7860775, 8946173, 12060141, 22816431). In at least one individual the data is consistent with the variant being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 3754). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. Experimental studies have shown that this missense change affects UROS function (PMID: 1737856, 30685241). For these reasons, this variant has been classified as Pathogenic. - |
UROS-related disorder Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Aug 25, 2022 | The UROS c.683C>T variant is predicted to result in the amino acid substitution p.Thr228Met. This variant has been reported in the compound heterozygous state in multiple individuals with autosomal recessive erythropoietic porphyria, and functional studies support its pathogenicity (Warner et al 1992. PubMed ID: 1737856; Fortian A et al 2009. PubMed ID: 19099412; Boulechfar S et al 1992. PubMed ID: 1733834; Fontanellas A et al. 1996. PubMed ID: 8946173). This variant is reported in 0.0057% of alleles in individuals of Latino descent in gnomAD (http://gnomad.broadinstitute.org/variant/10-127477552-G-A). This variant is interpreted as likely pathogenic. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at