rs2228084

chr1-45014037-A-G

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_000374.5(UROD):c.603A>G(p.Pro201=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.066 in 1,614,134 control chromosomes in the GnomAD database, including 4,074 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.086 (730 hom., cov: 32)
  • Exomes 𝑓: 0.064 (3344 hom.)
• Consequence: UROD NM_000374.5 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -0.440

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 Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.74).
• BP6: Variant 1-45014037-A-G is Benign according to our data. Variant chr1-45014037-A-G is described in ClinVar as [Benign]. Clinvar id is 255961.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-45014037-A-G is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-0.44 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.143 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
UROD	NM_000374.5	c.603A>G	p.Pro201=	synonymous_variant	6/10	ENST00000246337.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
UROD	ENST00000246337.9	c.603A>G	p.Pro201=	synonymous_variant	6/10	1	NM_000374.5	P1

Frequencies

GnomAD3 genomes AF: 0.0862 AC: 13111 AN: 152128 Hom.: 723 Cov.: 32

Gnomad AFR AF: 0.145

Gnomad AMI AF: 0.0691

Gnomad AMR AF: 0.0819

Gnomad ASJ AF: 0.0239

Gnomad EAS AF: 0.117

Gnomad SAS AF: 0.0555

Gnomad FIN AF: 0.0671

Gnomad MID AF: 0.0158

Gnomad NFE AF: 0.0582

Gnomad OTH AF: 0.0664

GnomAD3 exomes AF: 0.0758 AC: 19068 AN: 251476 Hom.: 911 AF XY: 0.0710 AC XY: 9653 AN XY: 135916

Gnomad AFR exome AF: 0.147

Gnomad AMR exome AF: 0.116

Gnomad ASJ exome AF: 0.0225

Gnomad EAS exome AF: 0.125

Gnomad SAS exome AF: 0.0593

Gnomad FIN exome AF: 0.0654

Gnomad NFE exome AF: 0.0575

Gnomad OTH exome AF: 0.0619

GnomAD4 exome AF: 0.0639 AC: 93456 AN: 1461888 Hom.: 3344 Cov.: 34 AF XY: 0.0627 AC XY: 45597 AN XY: 727246

Gnomad4 AFR exome AF: 0.146

Gnomad4 AMR exome AF: 0.111

Gnomad4 ASJ exome AF: 0.0221

Gnomad4 EAS exome AF: 0.115

Gnomad4 SAS exome AF: 0.0597

Gnomad4 FIN exome AF: 0.0689

Gnomad4 NFE exome AF: 0.0590

Gnomad4 OTH exome AF: 0.0617

GnomAD4 genome AF: 0.0864 AC: 13154 AN: 152246 Hom.: 730 Cov.: 32 AF XY: 0.0870 AC XY: 6475 AN XY: 74422

Gnomad4 AFR AF: 0.146

Gnomad4 AMR AF: 0.0817

Gnomad4 ASJ AF: 0.0239

Gnomad4 EAS AF: 0.117

Gnomad4 SAS AF: 0.0556

Gnomad4 FIN AF: 0.0671

Gnomad4 NFE AF: 0.0582

Gnomad4 OTH AF: 0.0662

Alfa AF: 0.0632 Hom.: 784

Bravo AF: 0.0921

Asia WGS AF: 0.0770 AC: 269 AN: 3478

EpiCase AF: 0.0527

EpiControl AF: 0.0514

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 30, 2024

- -

Familial porphyria cutanea tarda Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.74
Cadd	Benign	3.1
Dann	Benign	0.66
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs2228084; hg19: chr1-45479709; COSMIC: COSV55800359; COSMIC: COSV55800359;