Genetic Variant UROD:c.21-10T>A (chr1-45012897-T-A) – ACMG Classification: Uncertain_significance (4 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PP3_Strong

The NM_000374.5(UROD):c.21-10T>A variant causes a intron change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.0020 ( 0 hom., cov: 32)

Exomes 𝑓: 0.20 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

UROD
NM_000374.5 intron

Scores

Splicing: ADA: 0.9999

Clinical Significance

Uncertain significance criteria provided, single submitter U:1B:1

Conservation

PhyloP100: 0.445

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 4 ACMG points.

PP3

Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF, max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
UROD	NM_000374.5 link	c.21-10T>A		intron_variant	Intron 1 of 9	ENST00000246337.9	NP_000365.3	P06132

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
UROD	ENST00000246337.9 link	c.21-10T>A		intron_variant	Intron 1 of 9	1	NM_000374.5	ENSP00000246337.4		P06132

Frequencies

GnomAD3 genomes

AF:

0.00

AC:

278

AN:

141466

Hom.:

Cov.:

FAILED QC

Gnomad AFR

AF:

0.00119

Gnomad AMI

AF:

0.00115

Gnomad AMR

AF:

0.00126

Gnomad ASJ

AF:

0.00271

Gnomad EAS

AF:

0.00664

Gnomad SAS

AF:

0.00545

Gnomad FIN

AF:

0.00258

Gnomad MID

AF:

0.00331

Gnomad NFE

AF:

0.00196

Gnomad OTH

AF:

0.00151

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.195

AC:

161783

AN:

828142

Hom.:

Cov.:

AF XY:

0.180

AC XY:

76742

AN XY:

426990

show subpopulations

Gnomad4 AFR exome

AF:

0.161

Gnomad4 AMR exome

AF:

0.0244

Gnomad4 ASJ exome

AF:

0.111

Gnomad4 EAS exome

AF:

0.111

Gnomad4 SAS exome

AF:

0.0390

Gnomad4 FIN exome

AF:

0.0424

Gnomad4 NFE exome

AF:

0.244

Gnomad4 OTH exome

AF:

0.184

GnomAD4 genome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.00196

AC:

278

AN:

141562

Hom.:

Cov.:

AF XY:

0.00218

AC XY:

150

AN XY:

68718

show subpopulations

Gnomad4 AFR

AF:

0.00118

Gnomad4 AMR

AF:

0.00126

Gnomad4 ASJ

AF:

0.00271

Gnomad4 EAS

AF:

0.00640

Gnomad4 SAS

AF:

0.00545

Gnomad4 FIN

AF:

0.00258

Gnomad4 NFE

AF:

0.00198

Gnomad4 OTH

AF:

0.00149

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

UROD-related inherited porphyria

Uncertain:1

Apr 25, 2023

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: research

- -

UROD-related disorder

Benign:1

Aug 08, 2023

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.70

CADD

Benign

DANN

Benign

0.78

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

1.0

dbscSNV1_RF

Pathogenic

0.95

SpliceAI score (max)

0.99

Details are displayed if max score is > 0.2

DS_AG_spliceai

0.99

Position offset: 2

DS_AL_spliceai

0.76

Position offset: 10

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