1-45012282-T-A

Variant names:

• chr1-45012282-T-A
• NM_000374.5:c.17T>A

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1 PM2 PP5_Moderate

The NM_000374.5(UROD):​c.17T>A​(p.Leu6*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: UROD NM_000374.5 stop_gained
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: -0.701

Genes affected

UROD (HGNC:12591): (uroporphyrinogen decarboxylase) This gene encodes an enzyme in the heme biosynthetic pathway. This enzyme is responsible for catalyzing the conversion of uroporphyrinogen to coproporphyrinogen through the removal of four carboxymethyl side chains. Mutations and deficiency in this enzyme are known to cause familial porphyria cutanea tarda and hepatoerythropoetic porphyria.[provided by RefSeq, Aug 2010]

ACMG classification

Verdict is Pathogenic. Variant got 12 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant located near the start codon (<100nt), not predicted to undergo nonsense mediated mRNA decay. There are 66 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 1-45012282-T-A is Pathogenic according to our data. Variant chr1-45012282-T-A is described in ClinVar as [Pathogenic]. Clinvar id is 3727193.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
UROD	NM_000374.5	c.17T>A	p.Leu6*	stop_gained	Exon 1 of 10	ENST00000246337.9	NP_000365.3
UROD	NR_036510.2	n.29T>A		non_coding_transcript_exon_variant	Exon 1 of 10
UROD	NR_158184.1	n.29T>A		non_coding_transcript_exon_variant	Exon 1 of 10
UROD	NR_158185.1	n.29T>A		non_coding_transcript_exon_variant	Exon 1 of 10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
UROD	ENST00000246337.9	c.17T>A	p.Leu6*	stop_gained	Exon 1 of 10	1	NM_000374.5	ENSP00000246337.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Pathogenic:1

Dec 12, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change creates a premature translational stop signal (p.Leu6*) in the UROD gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in UROD are known to be pathogenic (PMID: 1634232, 17240319, 19233912, 19419417, 23545314). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with UROD-related conditions. For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.62	D
BayesDel_noAF	Benign	-0.24
CADD	Pathogenic	36
DANN	Benign	0.92
Eigen	Benign	-0.29
Eigen_PC	Benign	-0.70
FATHMM_MKL	Benign	0.28	N
Vest4		0.31
GERP RS		-4.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.12		Details are displayed if max score is > 0.2

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr1-45477954;