rs74349352

Variant names:

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

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

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:4

Conservation

PhyloP100: -1.01

Publications

4 publications found

Variant links:

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

UROD links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
UROD	NM_000374.5 link	c.*3G>A		3_prime_UTR_variant	Exon 10 of 10	ENST00000246337.9	NP_000365.3	P06132

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
UROD	ENST00000246337.9 link	c.*3G>A		3_prime_UTR_variant	Exon 10 of 10	1	NM_000374.5	ENSP00000246337.4		P06132

Frequencies

GnomAD3 genomes

AF:

0.00875

AC:

1331

AN:

152192

Hom.:

Cov.:

show subpopulations

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

show subpopulations

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.:

AF XY:

0.0113

AC XY:

8253

AN XY:

727246

show subpopulations

African (AFR)

AF:

0.00128

AC:

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:

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:

AN:

5768

European-Non Finnish (NFE)

AF:

0.0130

AC:

14500

AN:

1112012

Other (OTH)

AF:

0.0105

AC:

632

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.478

Heterozygous variant carriers

1003

2005

3008

4010

5013

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

540

1080

1620

2160

2700

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00874

AC:

1331

AN:

152310

Hom.:

Cov.:

AF XY:

0.00845

AC XY:

629

AN XY:

74472

show subpopulations

African (AFR)

AF:

0.00214

AC:

AN:

41558

American (AMR)

AF:

0.0103

AC:

158

AN:

15300

Ashkenazi Jewish (ASJ)

AF:

0.0144

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5188

South Asian (SAS)

AF:

0.00228

AC:

AN:

4834

European-Finnish (FIN)

AF:

0.0122

AC:

129

AN:

10612

Middle Eastern (MID)

AF:

0.00340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0127

AC:

865

AN:

68024

Other (OTH)

AF:

0.0132

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

152

227

303

379

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0111

Hom.:

Bravo

AF:

0.00852

Asia WGS

AF:

0.00115

AC:

AN:

3478

EpiCase

AF:

0.0131

EpiControl

AF:

0.0123

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:4

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:1Benign:2

Jan 19, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jun 12, 2023

Mayo Clinic Laboratories, Mayo Clinic

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

BS1, BP2 -

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

not specified

Benign:1

PreventionGenetics, part of Exact Sciences

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Familial porphyria cutanea tarda

Benign:1

Mar 06, 2018

Illumina Laboratory Services, Illumina

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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

(source)

DANN

Benign

0.79

PhyloP100

-1.0

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Mutation Taster

=100/0

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over