10-125788916-GGCTTGTGGCGTGGGGCTCTCTGCAGTGCAGCTTACAGGAAGGCCCTGGGCGGCCAGC-G

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM1 PM2 PM4 PP5_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
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• 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]

ACMG classification

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

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

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: dbNSFP v4.3

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs1850723875; hg19: chr10-127477485;