rs74349352

Variant names:

• chr1-45015501-G-A
• rs74349352
• NM_000374.5:c.*3G>A

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_000374.5(UROD):​c.*3G>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0112 in 1,614,194 control chromosomes in the GnomAD database, including 127 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0087 (4 hom., cov: 32)
  • Exomes 𝑓: 0.011 (123 hom.)
• Consequence: UROD NM_000374.5 3_prime_UTR
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:4
• Conservation: PhyloP100: -1.01
• Publications: 4 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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.85).
• BP6: Variant 1-45015501-G-A is Benign according to our data. Variant chr1-45015501-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 255960.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00874 (1331/152310) while in subpopulation NFE AF = 0.0127 (865/68024). AF 95% confidence interval is 0.012. There are 4 homozygotes in GnomAd4. There are 629 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 4 AD,SD,AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000374.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	UROD	NM_000374.5	MANE Select	c.*3G>A		3_prime_UTR	Exon 10 of 10	NP_000365.3
	UROD	NR_036510.2		n.1169G>A		non_coding_transcript_exon	Exon 10 of 10
	UROD	NR_158184.1		n.1188G>A		non_coding_transcript_exon	Exon 10 of 10

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	UROD	ENST00000246337.9	TSL:1 MANE Select	c.*3G>A		3_prime_UTR	Exon 10 of 10	ENSP00000246337.4
	UROD	ENST00000894914.1		c.*3G>A		3_prime_UTR	Exon 10 of 10	ENSP00000564973.1
	UROD	ENST00000894916.1		c.*3G>A		3_prime_UTR	Exon 9 of 9	ENSP00000564975.1

Frequencies

GnomAD3 genomes AF: 0.00875 AC: 1331 AN: 152192 Hom.: 4 Cov.: 32

Gnomad AFR AF: 0.00215

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0103

Gnomad ASJ AF: 0.0144

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00227

Gnomad FIN AF: 0.0122

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0127

Gnomad OTH AF: 0.0134

GnomAD2 exomes AF: 0.00972 AC: 2445 AN: 251470 AF XY: 0.00978

Gnomad AFR exome AF: 0.00135

Gnomad AMR exome AF: 0.00766

Gnomad ASJ exome AF: 0.0114

Gnomad EAS exome AF: 0.0000544

Gnomad FIN exome AF: 0.0139

Gnomad NFE exome AF: 0.0140

Gnomad OTH exome AF: 0.0111

GnomAD4 exome AF: 0.0115 AC: 16807 AN: 1461884 Hom.: 123 Cov.: 31 AF XY: 0.0113 AC XY: 8253 AN XY: 727246

African (AFR) AF: 0.00128 AC: 43 AN: 33480

American (AMR) AF: 0.00731 AC: 327 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0116 AC: 304 AN: 26136

East Asian (EAS) AF: 0.0000504 AC: 2 AN: 39700

South Asian (SAS) AF: 0.00292 AC: 252 AN: 86258

European-Finnish (FIN) AF: 0.0133 AC: 713 AN: 53410

Middle Eastern (MID) AF: 0.00589 AC: 34 AN: 5768

European-Non Finnish (NFE) AF: 0.0130 AC: 14500 AN: 1112012

Other (OTH) AF: 0.0105 AC: 632 AN: 60396

GnomAD4 genome AF: 0.00874 AC: 1331 AN: 152310 Hom.: 4 Cov.: 32 AF XY: 0.00845 AC XY: 629 AN XY: 74472

African (AFR) AF: 0.00214 AC: 89 AN: 41558

American (AMR) AF: 0.0103 AC: 158 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.0144 AC: 50 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5188

South Asian (SAS) AF: 0.00228 AC: 11 AN: 4834

European-Finnish (FIN) AF: 0.0122 AC: 129 AN: 10612

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.0127 AC: 865 AN: 68024

Other (OTH) AF: 0.0132 AC: 28 AN: 2116

Alfa AF: 0.0111 Hom.: 8

Bravo AF: 0.00852

Asia WGS AF: 0.00115 AC: 4 AN: 3478

EpiCase AF: 0.0131

EpiControl AF: 0.0123

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	0.040
DANN	Benign	0.79
PhyloP100		-1.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=100/0	polymorphism

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: rs74349352; hg19: chr1-45481173;