1-45012956-T-G

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_000374.5(UROD):c.70T>G(p.Trp24Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: UROD NM_000374.5 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 2.28

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 Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.39842987).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
UROD	NM_000374.5	c.70T>G	p.Trp24Gly	missense_variant	2/10	ENST00000246337.9
UROD	NR_036510.2	n.132T>G		non_coding_transcript_exon_variant	2/10
UROD	NR_158184.1	n.132T>G		non_coding_transcript_exon_variant	2/10
UROD	NR_158185.1	n.82T>G		non_coding_transcript_exon_variant	2/10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
UROD	ENST00000246337.9	c.70T>G	p.Trp24Gly	missense_variant	2/10	1	NM_000374.5	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 36

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Jan 19, 2024

This sequence change replaces tryptophan, which is neutral and slightly polar, with glycine, which is neutral and non-polar, at codon 24 of the UROD protein (p.Trp24Gly). 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. ClinVar contains an entry for this variant (Variation ID: 1683505). 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 UROD protein function with a negative predictive value of 80%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Familial porphyria cutanea tarda Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein

Jan 24, 2022

ACMG classification criteria: PM2 moderate, PM3 supporting -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Uncertain	0.15	D
BayesDel_noAF	Uncertain	-0.030
Cadd	Uncertain	26
Dann	Benign	0.94
DEOGEN2	Uncertain	0.56	D;T;T;T
Eigen	Benign	0.15
Eigen_PC	Uncertain	0.31
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.96	D;D;D;.
M_CAP	Uncertain	0.14	D
MetaRNN	Benign	0.40	T;T;T;T
MetaSVM	Uncertain	0.43	D
MutationAssessor	Benign	1.1	L;.;.;.
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.64	T
PROVEAN	Benign	-0.20	N;.;.;N
REVEL	Uncertain	0.43
Sift	Uncertain	0.014	D;.;.;D
Sift4G	Uncertain	0.050	T;.;.;T
Polyphen		0.0060	B;.;.;.
Vest4		0.41
MutPred		0.50		Gain of disorder (P = 0.0134);Gain of disorder (P = 0.0134);Gain of disorder (P = 0.0134);Gain of disorder (P = 0.0134);
MVP		0.97
MPC		1.1
ClinPred		0.77	D
GERP RS		6.1
Varity_R		0.60
gMVP		0.81

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: chr1-45478628;