rs121908014

Positions:

chr10-125788983-G-A

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PM1PM2PP3_StrongPP5

The NM_000375.3(UROS):c.683C>T(p.Thr228Met) variant causes a missense change. The variant allele was found at a frequency of 0.0000285 in 1,612,774 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 Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.000033 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000028 ( 0 hom. )

Consequence

UROS
NM_000375.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:3U:1

Conservation

PhyloP100: 5.78

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 9 ACMG points.

PM1

In a mutagenesis_site Impairs enzymatic activity. (size 0) in uniprot entity HEM4_HUMAN

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.99

PP5

Variant 10-125788983-G-A is Pathogenic according to our data. Variant chr10-125788983-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 3754.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=1, Uncertain_significance=1, Pathogenic=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
UROS	NM_000375.3 linkuse as main transcript	c.683C>T	p.Thr228Met	missense_variant	10/10	ENST00000368797.10	NP_000366.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
UROS	ENST00000368797.10 linkuse as main transcript	c.683C>T	p.Thr228Met	missense_variant	10/10	1	NM_000375.3	ENSP00000357787	P1

Frequencies

GnomAD3 genomes

AF:

0.0000328

AC:

AN:

152238

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000131

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:

0.0000147

Gnomad OTH

AF:

0.000478

GnomAD3 exomes

AF:

0.0000162

AC:

AN:

246592

Hom.:

AF XY:

0.0000149

AC XY:

AN XY:

134200

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000580

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:

0.0000181

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000281

AC:

AN:

1460536

Hom.:

Cov.:

AF XY:

0.0000275

AC XY:

AN XY:

726536

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.0000671

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000297

Gnomad4 OTH exome

AF:

0.0000331

GnomAD4 genome

AF:

0.0000328

AC:

AN:

152238

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74374

show subpopulations

Gnomad4 AFR

AF:

0.0000241

Gnomad4 AMR

AF:

0.000131

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.000478

Alfa

AF:

0.0000399

Hom.:

Bravo

AF:

0.0000567

ExAC

AF:

0.0000248

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:3Uncertain:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Cutaneous porphyria

Pathogenic:1Uncertain:1

Pathogenic, no assertion criteria provided	literature only	OMIM	Jan 01, 1992	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Sep 07, 2022	- -

not provided

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Aug 27, 2021

This sequence change replaces threonine with methionine at codon 228 of the UROS protein (p.Thr228Met). The threonine residue is highly conserved and there is a moderate physicochemical difference between threonine and methionine. This variant is present in population databases (rs121908014, ExAC 0.02%). This missense change has been observed in individual(s) with congenital erythropoietic porphyria (PMID: 1737856, 7860775, 8946173, 12060141, 22816431). In at least one individual the data is consistent with the variant being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 3754). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. Experimental studies have shown that this missense change affects UROS function (PMID: 1737856, 30685241). For these reasons, this variant has been classified as Pathogenic. -

UROS-related disorder

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Aug 25, 2022

The UROS c.683C>T variant is predicted to result in the amino acid substitution p.Thr228Met. This variant has been reported in the compound heterozygous state in multiple individuals with autosomal recessive erythropoietic porphyria, and functional studies support its pathogenicity (Warner et al 1992. PubMed ID: 1737856; Fortian A et al 2009. PubMed ID: 19099412; Boulechfar S et al 1992. PubMed ID: 1733834; Fontanellas A et al. 1996. PubMed ID: 8946173). This variant is reported in 0.0057% of alleles in individuals of Latino descent in gnomAD (http://gnomad.broadinstitute.org/variant/10-127477552-G-A). This variant is interpreted as likely pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.80

BayesDel_addAF

Pathogenic

0.42

BayesDel_noAF

Pathogenic

0.54

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

0.96

D;D;D;.;.

Eigen

Pathogenic

0.89

Eigen_PC

Pathogenic

0.80

FATHMM_MKL

Uncertain

0.94

LIST_S2

Uncertain

0.95

.;.;D;D;D

M_CAP

Pathogenic

0.50

MetaRNN

Pathogenic

0.99

D;D;D;D;D

MetaSVM

Pathogenic

1.1

MutationAssessor

Pathogenic

3.7

H;H;H;.;.

MutationTaster

Benign

1.0

A;A

PrimateAI

Uncertain

0.49

PROVEAN

Pathogenic

-5.4

D;.;D;.;.

REVEL

Pathogenic

0.95

Sift

Pathogenic

0.0

D;.;D;.;.

Sift4G

Pathogenic

0.0

D;.;D;.;.

Polyphen

1.0

D;D;D;.;.

Vest4

0.94

MutPred

0.94

Loss of catalytic residue at T228 (P = 0.0553);Loss of catalytic residue at T228 (P = 0.0553);Loss of catalytic residue at T228 (P = 0.0553);.;Loss of catalytic residue at T228 (P = 0.0553);

MVP

0.99

MPC

0.48

ClinPred

0.99

GERP RS

4.9

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.93

gMVP

0.96

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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