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

Scores

Not classified

Clinical Significance

Pathogenic criteria provided, single submitter P:1

Conservation

PhyloP100: 5.79
Variant links:
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;
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
UROSNM_000375.3 linkuse as main transcriptc.693_749del p.Leu232_Ala250del inframe_deletion 10/10 ENST00000368797.10

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
UROSENST00000368797.10 linkuse as main transcriptc.693_749del p.Leu232_Ala250del inframe_deletion 10/101 NM_000375.3 P1

Frequencies

GnomAD3 genomes
Cov.:
33
We have no GnomAD4 exomes data on this position. Probably position not covered by the project.
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 submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpJul 17, 2023This 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: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs1850723875; hg19: chr10-127477485; API