rs121908020
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Variant summary
Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM1PM2PP3_ModeratePP5_Moderate
The NM_000375.3(UROS):c.673G>A(p.Gly225Ser) variant causes a missense change. The variant allele was found at a frequency of 0.0000806 in 1,612,916 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 0.000066 ( 0 hom., cov: 33)
Exomes 𝑓: 0.000082 ( 0 hom. )
Consequence
UROS
NM_000375.3 missense
NM_000375.3 missense
Scores
13
4
1
Clinical Significance
Conservation
PhyloP100: 4.53
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 Likely_pathogenic. Variant got 8 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, 0.931
PP5
?
Variant 10-125788993-C-T is Pathogenic according to our data. Variant chr10-125788993-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 3766.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr10-125788993-C-T is described in Lovd as [Pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
UROS | NM_000375.3 | c.673G>A | p.Gly225Ser | missense_variant | 10/10 | ENST00000368797.10 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
UROS | ENST00000368797.10 | c.673G>A | p.Gly225Ser | missense_variant | 10/10 | 1 | NM_000375.3 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.0000657 AC: 10AN: 152204Hom.: 0 Cov.: 33
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GnomAD3 exomes AF: 0.0000365 AC: 9AN: 246374Hom.: 0 AF XY: 0.0000522 AC XY: 7AN XY: 134182
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GnomAD4 exome AF: 0.0000822 AC: 120AN: 1460594Hom.: 0 Cov.: 30 AF XY: 0.0000853 AC XY: 62AN XY: 726572
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GnomAD4 genome ? AF: 0.0000657 AC: 10AN: 152322Hom.: 0 Cov.: 33 AF XY: 0.0000403 AC XY: 3AN XY: 74474
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ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:2Other:1
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
Cutaneous porphyria Pathogenic:1Other:1
Pathogenic, no assertion criteria provided | literature only | OMIM | Mar 01, 2001 | - - |
not provided, no classification provided | literature only | GeneReviews | - | - - |
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Dec 02, 2023 | This sequence change replaces glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 225 of the UROS protein (p.Gly225Ser). This variant is present in population databases (rs121908020, gnomAD 0.006%). This missense change has been observed in individuals with congenital erythropoietic porphyria (PMID: 7860775, 16365260). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 3766). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt UROS protein function with a negative predictive value of 80%. Experimental studies have shown that this missense change affects UROS function (PMID: 7860775, 19099412). For these reasons, this variant has been classified as Pathogenic. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Uncertain
DEOGEN2
Pathogenic
D;D;D;.;.
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Uncertain
D
M_CAP
Pathogenic
D
MetaRNN
Pathogenic
D;D;D;D;D
MetaSVM
Pathogenic
D
MutationAssessor
Pathogenic
H;H;H;.;.
MutationTaster
Benign
A;A
PrimateAI
Uncertain
T
PROVEAN
Pathogenic
D;.;D;.;.
REVEL
Pathogenic
Sift
Uncertain
D;.;D;.;.
Sift4G
Pathogenic
D;.;D;.;.
Polyphen
D;D;D;.;.
Vest4
MVP
MPC
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