chr10-125788916-GGCTTGTGGCGTGGGGCTCTCTGCAGTGCAGCTTACAGGAAGGCCCTGGGCGGCCAGC-G
Variant summary
Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM1PM2PM4PP5_Moderate
The NM_000375.3(UROS):c.693_749del(p.Leu232_Ala250del) variant causes a inframe deletion change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★). Synonymous variant affecting the same amino acid position (i.e. A231A) has been classified as Likely benign.
Frequency
Genomes: not found (cov: 33)
Consequence
UROS
NM_000375.3 inframe_deletion
NM_000375.3 inframe_deletion
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 5.79
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]
Genome browser will be placed here
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;
PM4
Nonframeshift variant in NON repetitive region in NM_000375.3.
PP5
Variant 10-125788916-GGCTTGTGGCGTGGGGCTCTCTGCAGTGCAGCTTACAGGAAGGCCCTGGGCGGCCAGC-G is Pathogenic according to our data. Variant chr10-125788916-GGCTTGTGGCGTGGGGCTCTCTGCAGTGCAGCTTACAGGAAGGCCCTGGGCGGCCAGC-G is described in ClinVar as [Pathogenic]. Clinvar id is 1002289.Status of the report is criteria_provided_single_submitter, 1 stars.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
UROS | NM_000375.3 | c.693_749del | p.Leu232_Ala250del | inframe_deletion | 10/10 | ENST00000368797.10 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
UROS | ENST00000368797.10 | c.693_749del | p.Leu232_Ala250del | inframe_deletion | 10/10 | 1 | NM_000375.3 | P1 |
Frequencies
GnomAD3 genomes Cov.: 33
GnomAD3 genomes
Cov.:
33
We have no GnomAD4 exomes data on this position. Probably position not covered by the project.
GnomAD4 genome Cov.: 33
GnomAD4 genome
Cov.:
33
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 | Jul 17, 2023 | This variant has been observed in individual(s) with congenital erythropoietic porphyria (Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is not present in population databases (gnomAD no frequency). This variant, c.693_749del, results in the deletion of 19 amino acid(s) of the UROS protein (p.Ala234_Ala252del), but otherwise preserves the integrity of the reading frame. ClinVar contains an entry for this variant (Variation ID: 1002289). This variant disrupts a region of the UROS protein in which other variant(s) (p.Leu237Pro) have been determined to be pathogenic (PMID: 17298225, 19099412, 22350154, 22816431). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at