rs36033115

Positions:

chr1-45014560-T-A

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_000374.5(UROD):c.758T>A(p.Leu253Gln) variant causes a missense change. The variant allele was found at a frequency of 0.00576 in 1,614,198 control chromosomes in the GnomAD database, including 36 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 0.0052 ( 5 hom., cov: 33)

Exomes 𝑓: 0.0058 ( 31 hom. )

Consequence

UROD
NM_000374.5 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:2

Conservation

PhyloP100: 3.89

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 links:

UROD (HGNC:):

UROD links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0076975226).

BP6

Variant 1-45014560-T-A is Benign according to our data. Variant chr1-45014560-T-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 297463.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=1, Benign=1}. Variant chr1-45014560-T-A is described in Lovd as [Benign].

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00519 (790/152328) while in subpopulation NFE AF= 0.00623 (424/68028). AF 95% confidence interval is 0.00574. There are 5 homozygotes in gnomad4. There are 449 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 5 SD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
UROD	NM_000374.5 linkuse as main transcript	c.758T>A	p.Leu253Gln	missense_variant	7/10	ENST00000246337.9	NP_000365.3	P06132

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
UROD	ENST00000246337.9 linkuse as main transcript	c.758T>A	p.Leu253Gln	missense_variant	7/10	1	NM_000374.5	ENSP00000246337.4		P06132

Frequencies

GnomAD3 genomes

AF:

0.00519

AC:

790

AN:

152210

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00111

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000785

Gnomad ASJ

AF:

0.00231

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00124

Gnomad FIN

AF:

0.0268

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.00623

Gnomad OTH

AF:

0.00430

GnomAD3 exomes

AF:

0.00580

AC:

1458

AN:

251286

Hom.:

AF XY:

0.00573

AC XY:

778

AN XY:

135816

show subpopulations

Gnomad AFR exome

AF:

0.000616

Gnomad AMR exome

AF:

0.00119

Gnomad ASJ exome

AF:

0.00357

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000653

Gnomad FIN exome

AF:

0.0239

Gnomad NFE exome

AF:

0.00709

Gnomad OTH exome

AF:

0.00472

GnomAD4 exome

AF:

0.00582

AC:

8502

AN:

1461870

Hom.:

Cov.:

AF XY:

0.00571

AC XY:

4149

AN XY:

727234

show subpopulations

Gnomad4 AFR exome

AF:

0.000657

Gnomad4 AMR exome

AF:

0.00134

Gnomad4 ASJ exome

AF:

0.00386

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000962

Gnomad4 FIN exome

AF:

0.0230

Gnomad4 NFE exome

AF:

0.00603

Gnomad4 OTH exome

AF:

0.00482

GnomAD4 genome

AF:

0.00519

AC:

790

AN:

152328

Hom.:

Cov.:

AF XY:

0.00603

AC XY:

449

AN XY:

74498

show subpopulations

Gnomad4 AFR

AF:

0.00111

Gnomad4 AMR

AF:

0.000784

Gnomad4 ASJ

AF:

0.00231

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00124

Gnomad4 FIN

AF:

0.0268

Gnomad4 NFE

AF:

0.00623

Gnomad4 OTH

AF:

0.00426

Alfa

AF:

0.00544

Hom.:

Bravo

AF:

0.00325

TwinsUK

AF:

0.00539

AC:

ALSPAC

AF:

0.00493

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.00814

AC:

ExAC

AF:

0.00583

AC:

708

Asia WGS

AF:

0.000577

AC:

AN:

3478

EpiCase

AF:

0.00578

EpiControl

AF:

0.00634

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Familial porphyria cutanea tarda

Uncertain:1Benign: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. -
Uncertain significance, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -

not provided

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 25, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Benign

-0.18

BayesDel_noAF

Uncertain

-0.020

CADD

Uncertain

DANN

Benign

0.94

DEOGEN2

Uncertain

0.75

D;T

Eigen

Benign

-0.048

Eigen_PC

Benign

0.13

FATHMM_MKL

Uncertain

0.85

LIST_S2

Uncertain

0.94

D;D

MetaRNN

Benign

0.0077

T;T

MetaSVM

Uncertain

0.10

MutationAssessor

Uncertain

2.3

M;.

PrimateAI

Benign

0.46

PROVEAN

Benign

-1.7

N;.

REVEL

Uncertain

0.51

Sift

Benign

0.056

T;.

Sift4G

Benign

0.51

T;.

Polyphen

0.057

B;.

Vest4

0.72

MVP

0.96

MPC

0.44

ClinPred

0.016

GERP RS

5.2

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.46

gMVP

0.79

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.030

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