rs2228084

Variant names:

• chr1-45014037-A-G
• rs2228084
• NM_000374.5:c.603A>G

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The ENST00000246337.9(UROD):​c.603A>G​(p.Pro201Pro) 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 (★★). Synonymous variant affecting the same amino acid position (i.e. P201P) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.086 (730 hom., cov: 32)
  • Exomes 𝑓: 0.064 (3344 hom.)
• Consequence: UROD ENST00000246337.9 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -0.440
• Publications: 13 publications found

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]

UROD Gene-Disease associations (from GenCC):

• UROD-related inherited porphyria

  Inheritance: SD Classification: DEFINITIVE Submitted by: ClinGen, Ambry Genetics
• familial porphyria cutanea tarda

  Inheritance: AD, AR Classification: STRONG, SUPPORTIVE Submitted by: Genomics England PanelApp, Orphanet, Labcorp Genetics (formerly Invitae)
• hepatoerythropoietic porphyria

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -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 VariationId is 255961.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• 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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000246337.9. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	UROD	NM_000374.5	MANE Select	c.603A>G	p.Pro201Pro	synonymous	Exon 6 of 10	NP_000365.3
	UROD	NR_036510.2		n.665A>G		non_coding_transcript_exon	Exon 6 of 10
	UROD	NR_158184.1		n.684A>G		non_coding_transcript_exon	Exon 6 of 10

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	UROD	ENST00000246337.9	TSL:1 MANE Select	c.603A>G	p.Pro201Pro	synonymous	Exon 6 of 10	ENSP00000246337.4
	UROD	ENST00000652287.1		c.540A>G	p.Pro180Pro	synonymous	Exon 5 of 9	ENSP00000498413.1
	UROD	ENST00000651476.1		c.498A>G	p.Pro166Pro	synonymous	Exon 6 of 10	ENSP00000498668.1

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

GnomAD2 exomes AF: 0.0758 AC: 19068 AN: 251476 AF XY: 0.0710

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 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

African (AFR) AF: 0.146 AC: 4881 AN: 33480

American (AMR) AF: 0.111 AC: 4956 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0221 AC: 577 AN: 26136

East Asian (EAS) AF: 0.115 AC: 4583 AN: 39700

South Asian (SAS) AF: 0.0597 AC: 5149 AN: 86258

European-Finnish (FIN) AF: 0.0689 AC: 3682 AN: 53418

Middle Eastern (MID) AF: 0.0439 AC: 253 AN: 5768

European-Non Finnish (NFE) AF: 0.0590 AC: 65647 AN: 1112008

Other (OTH) AF: 0.0617 AC: 3728 AN: 60396

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

African (AFR) AF: 0.146 AC: 6066 AN: 41518

American (AMR) AF: 0.0817 AC: 1249 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.0239 AC: 83 AN: 3472

East Asian (EAS) AF: 0.117 AC: 605 AN: 5182

South Asian (SAS) AF: 0.0556 AC: 268 AN: 4822

European-Finnish (FIN) AF: 0.0671 AC: 712 AN: 10610

Middle Eastern (MID) AF: 0.0204 AC: 6 AN: 294

European-Non Finnish (NFE) AF: 0.0582 AC: 3962 AN: 68028

Other (OTH) AF: 0.0662 AC: 140 AN: 2116

Alfa AF: 0.0669 Hom.: 1747

Bravo AF: 0.0921

Asia WGS AF: 0.0770 AC: 269 AN: 3478

EpiCase AF: 0.0527

EpiControl AF: 0.0514

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not specified (3)
-	-	2	not provided (2)
-	-	1	Familial porphyria cutanea tarda (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.74
CADD	Benign	3.1
DANN	Benign	0.66
PhyloP100		-0.44
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

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