rs74349352

chr1-45015501-G-A

Variant summary

Our verdict is Benign. Variant got -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:3
• Conservation: PhyloP100: -1.01

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 -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 id is 255960.We mark this variant Likely_benign, oryginal submissions are: {Benign=1, Likely_benign=2, Uncertain_significance=1}.
• 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 male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 4 SD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
UROD	NM_000374.5	c.*3G>A		3_prime_UTR_variant	10/10	ENST00000246337.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
UROD	ENST00000246337.9	c.*3G>A		3_prime_UTR_variant	10/10	1	NM_000374.5	P1

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

GnomAD3 exomes AF: 0.00972 AC: 2445 AN: 251470 Hom.: 10 AF XY: 0.00978 AC XY: 1329 AN XY: 135914

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 SAS exome AF: 0.00274

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

Gnomad4 AFR exome AF: 0.00128

Gnomad4 AMR exome AF: 0.00731

Gnomad4 ASJ exome AF: 0.0116

Gnomad4 EAS exome AF: 0.0000504

Gnomad4 SAS exome AF: 0.00292

Gnomad4 FIN exome AF: 0.0133

Gnomad4 NFE exome AF: 0.0130

Gnomad4 OTH exome AF: 0.0105

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

Gnomad4 AFR AF: 0.00214

Gnomad4 AMR AF: 0.0103

Gnomad4 ASJ AF: 0.0144

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00228

Gnomad4 FIN AF: 0.0122

Gnomad4 NFE AF: 0.0127

Gnomad4 OTH AF: 0.0132

Alfa AF: 0.0109 Hom.: 6

Bravo AF: 0.00852

Asia WGS AF: 0.00115 AC: 4 AN: 3478

EpiCase AF: 0.0131

EpiControl AF: 0.0123

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:3

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1 Benign:1

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 20, 2024	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Jun 12, 2023	BS1, BP2 -

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

-

- -

Familial porphyria cutanea tarda Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Mar 06, 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 likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
Cadd	Benign	0.040
Dann	Benign	0.79
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

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: rs74349352; hg19: chr1-45481173;