10-125815061-A-G

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PP3_ModeratePP5_Very_Strong

The NM_000375.3(UROS):c.217T>C(p.Cys73Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000265 in 1,614,220 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★).

Frequency

Genomes: 𝑓 0.00024 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00027 ( 0 hom. )

Consequence

UROS
NM_000375.3 missense

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:9O:1

Conservation

PhyloP100: 2.63

Publications

58 publications found

Variant links:

Genes affected

UROS (HGNC:12592): (uroporphyrinogen III synthase) The protein encoded by this gene catalyzes the fourth step of porphyrin biosynthesis in the heme biosynthetic pathway. Defects in this gene cause congenital erythropoietic porphyria (Gunther's disease). [provided by RefSeq, Jul 2008]

UROS Gene-Disease associations (from GenCC):

cutaneous porphyria
Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Genomics England PanelApp, Labcorp Genetics (formerly Invitae), G2P, Orphanet

UROS links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 10 ACMG points.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.855

PP5

Variant 10-125815061-A-G is Pathogenic according to our data. Variant chr10-125815061-A-G is described in ClinVar as Pathogenic. ClinVar VariationId is 3750.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
UROS	NM_000375.3 link	c.217T>C	p.Cys73Arg	missense_variant	Exon 4 of 10	ENST00000368797.10	NP_000366.1	P10746A0A0S2Z4T8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
UROS	ENST00000368797.10 link	c.217T>C	p.Cys73Arg	missense_variant	Exon 4 of 10	1	NM_000375.3	ENSP00000357787.4		P10746

Frequencies

GnomAD3 genomes

AF:

0.000250

AC:

AN:

152226

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000169

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000523

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000338

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000211

AC:

AN:

251462

AF XY:

0.000213

show subpopulations

Gnomad AFR exome

AF:

0.000123

Gnomad AMR exome

AF:

0.000174

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000396

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000267

AC:

391

AN:

1461876

Hom.:

Cov.:

AF XY:

0.000265

AC XY:

193

AN XY:

727238

show subpopulations

African (AFR)

AF:

0.0000299

AC:

AN:

33480

American (AMR)

AF:

0.000157

AC:

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26134

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.00

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.0000187

AC:

AN:

53416

Middle Eastern (MID)

AF:

0.000347

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.000336

AC:

374

AN:

1112002

Other (OTH)

AF:

0.0000993

AC:

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.464

Heterozygous variant carriers

111

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

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

GnomAD4 genome

AF:

0.000243

AC:

AN:

152344

Hom.:

Cov.:

AF XY:

0.000268

AC XY:

AN XY:

74500

show subpopulations

African (AFR)

AF:

0.000168

AC:

AN:

41574

American (AMR)

AF:

0.000523

AC:

AN:

15306

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5190

South Asian (SAS)

AF:

0.00

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10628

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000323

AC:

AN:

68028

Other (OTH)

AF:

0.00

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.495

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<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:

0.000291

Hom.:

Bravo

AF:

0.000261

TwinsUK

AF:

0.000539

AC:

ALSPAC

AF:

0.000259

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000698

AC:

ExAC

AF:

0.000148

AC:

EpiCase

AF:

0.000327

EpiControl

AF:

0.000415

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:9Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Cutaneous porphyria

Pathogenic:6Other:1

GeneReviews

Significance:not provided

Review Status:no classification provided

Collection Method:literature only

Most common UROS pathogenic variant observed in approximately one-third of affected persons. -

Mar 25, 2021

Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

ACMG classification criteria: PS3 supporting, PM3 very strong, PP3 supporting -

Apr 15, 2011

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Nov 12, 2019

Revvity Omics, Revvity

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Across a selection of the available literature, the UROS c.217T>C (p.Cys73Arg) missense variant has been identified in 17 individuals with congenital erythropoietic porphyria, including in six in a homozygous state, in seven in a compound heterozygous state, and in four in a heterozygous state (Deybach et al. 1990; Boulechfar et al. 1992; Warner et al. 1992; Xu et al. 1995; Frank et al. 1998). The p.Cys73Arg variant was also found in a heterozygous state in ten unaffected family members (Deybach et al. 1990; Boulechfar et al. 1992; Warner et al. 1992; Xu et al. 1995; Frank et al. 1998). The variant was absent from the only two controls tested and is reported at a frequency of 0.00069 in the European American population of the Exome Sequencing Project. Expression of the p.Cys73Arg variant in E. coli showed less than 2% residual protein activity (Boulechfar et al. 1992; Warner et al. 1992). Fortian et al. (2011) demonstrated that the p.Cys73Arg variant leads to irreversible enzyme unfolding and aggregation while Bishop et al. (2011) showed that knock-in mice homozygous for the p.Cys73Arg variant had a severe phenotype. Based on the collective evidence, the p.Cys73Arg variant is classified as pathogenic for congenital erythropoietic porphyria. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. -

Apr 03, 2024

Fulgent Genetics, Fulgent Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Sep 02, 2022

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with congenital erythropoietic porphyria (MIM#263700). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0200 - Variant is predicted to result in a missense amino acid change from cysteine to arginine. (I) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD <0.01 for a recessive condition (v2: 62 heterozygotes, 0 homozygotes). (SP) 0309 - An alternative amino acid change at the same position has been observed in gnomAD (v2: 1 heterozygote, 0 homozygotes). (I) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0600 - Variant is located in the annotated HEM4 family domain (DECIPHER). (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. It has been well reported as pathogenic, and as homozygous and compound heterozygous in affected individuals (ClinVar, PMIDs: 34828434, 31843562, 15065102, 30685241). (SP) 1002 - This variant has moderate functional evidence supporting abnormal protein function. Functional studies showed the C73R enzyme had markedly decreased UROS activity (PMID: 21570665). (SP) 1206 - This variant has been shown to be paternally inherited (by trio analysis). (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -

not provided

Pathogenic:2

Aug 31, 2016

Eurofins Ntd Llc (ga)

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Dec 17, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces cysteine, which is neutral and slightly polar, with arginine, which is basic and polar, at codon 73 of the UROS protein (p.Cys73Arg). This variant is present in population databases (rs121908012, gnomAD 0.04%). This missense change has been observed in individual(s) with congenital erythropoietic porphyria (PMID: 1737856, 8821859, 22816431, 23557135, 25092523, 27859603). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 3750). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt UROS protein function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects UROS function (PMID: 16532394, 19099412, 21343304). For these reasons, this variant has been classified as Pathogenic. -

UROS-related disorder

Pathogenic:1

Jun 25, 2024

PreventionGenetics, part of Exact Sciences

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

The UROS c.217T>C variant is predicted to result in the amino acid substitution p.Cys73Arg. This variant has been reported to be causative for congenital erythropoietic porphyria (Xu et al. 1995. PubMed ID: 7860775; Deybach et al. 1990. PubMed ID: 2331520; Glomglao et al. 2015. PubMed ID: 25092523). Homozygous mouse models of the p.Cys73Arg variant resulted in severe microcytic hypochromic anemia and congenital erythropoietic porphyria (Bishop et al. 2011. PubMed ID: 21365124). This variant is reported in 0.041% of alleles in individuals of European (Non-Finnish) descent in gnomAD. This variant is interpreted as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.84

BayesDel_addAF

Pathogenic

0.17

BayesDel_noAF

Pathogenic

0.33

CADD

Uncertain

(source)

DANN

Benign

0.96

DEOGEN2

Pathogenic

0.81

D;D;D;.;.;D;D;D

Eigen

Uncertain

0.34

Eigen_PC

Benign

0.22

FATHMM_MKL

Uncertain

0.79

LIST_S2

Benign

0.76

.;.;T;T;T;T;T;T

M_CAP

Uncertain

0.19

MetaRNN

Pathogenic

0.86

D;D;D;D;D;D;D;D

MetaSVM

Uncertain

0.75

MutationAssessor

Uncertain

2.3

M;M;M;.;.;.;.;.

PhyloP100

2.6

PrimateAI

Benign

0.45

PROVEAN

Pathogenic

-5.9

D;.;D;.;.;D;D;D

REVEL

Pathogenic

0.84

Sift

Uncertain

0.0020

D;.;D;.;.;D;D;D

Sift4G

Uncertain

0.014

D;.;D;.;.;.;D;D

Polyphen

0.99

D;D;D;.;.;.;.;.

Vest4

0.82

MVP

0.88

MPC

0.59

ClinPred

0.63

GERP RS

3.0

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.99

gMVP

0.92

Mutation Taster

=1/99

disease causing (ClinVar)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.040

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