10-125815061-A-G

Position:

chr10-125815061-A-G

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM1PM2PP3_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

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 links:

UROS (HGNC:):

UROS links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 14 ACMG points.

PM1

In a chain Uroporphyrinogen-III synthase (size 264) in uniprot entity HEM4_HUMAN there are 8 pathogenic changes around while only 1 benign (89%) in NM_000375.3

PM2

Very rare variant in population databases, with high coverage;

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 id is 3750.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
UROS	NM_000375.3 linkuse as main transcript	c.217T>C	p.Cys73Arg	missense_variant	4/10	ENST00000368797.10	NP_000366.1	P10746A0A0S2Z4T8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
UROS	ENST00000368797.10 linkuse as main transcript	c.217T>C	p.Cys73Arg	missense_variant	4/10	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

GnomAD3 exomes

AF:

0.000211

AC:

AN:

251462

Hom.:

AF XY:

0.000213

AC XY:

AN XY:

135908

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 SAS 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

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.000157

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.0000187

Gnomad4 NFE exome

AF:

0.000336

Gnomad4 OTH exome

AF:

0.0000993

GnomAD4 genome

AF:

0.000243

AC:

AN:

152344

Hom.:

Cov.:

AF XY:

0.000268

AC XY:

AN XY:

74500

show subpopulations

Gnomad4 AFR

AF:

0.000168

Gnomad4 AMR

AF:

0.000523

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000323

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000268

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

Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Nov 12, 2019	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Apr 15, 2011	- -
Pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Apr 03, 2024	- -
not provided, no classification provided	literature only	GeneReviews	-	Most common UROS pathogenic variant observed in approximately one-third of affected persons. -
Pathogenic, criteria provided, single submitter	clinical testing	Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein	Mar 25, 2021	ACMG classification criteria: PS3 supporting, PM3 very strong, PP3 supporting -
Pathogenic, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	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. -
Pathogenic, criteria provided, single submitter	clinical testing	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	Sep 02, 2022	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

Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 11, 2023	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). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on UROS protein function. 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. -
Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Aug 31, 2016	- -

UROS-related disorder

Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jun 25, 2024

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

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;.;.;.;.;.

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

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over