1-45012897-T-A

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 4P and 2B. PP3_Strong BP6_Moderate

The NM_000374.5(UROD):c.21-10T>A variant causes a splice polypyrimidine tract, 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 Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0020 (0 hom., cov: 32)
  • Exomes 𝑓: 0.20 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: UROD NM_000374.5 splice_polypyrimidine_tract, intron
• Scores: Splicing: ADA: 0.9999
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.445

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 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.
• BP6: Variant 1-45012897-T-A is Benign according to our data. Variant chr1-45012897-T-A is described in ClinVar as [Likely_benign]. Clinvar id is 3061020.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
UROD	NM_000374.5	c.21-10T>A		splice_polypyrimidine_tract_variant, intron_variant		ENST00000246337.9
UROD	NR_036510.2	n.73T>A		non_coding_transcript_exon_variant	2/10
UROD	NR_158184.1	n.73T>A		non_coding_transcript_exon_variant	2/10
UROD	NR_158185.1	n.33-10T>A		splice_polypyrimidine_tract_variant, intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
UROD	ENST00000246337.9	c.21-10T>A		splice_polypyrimidine_tract_variant, intron_variant		1	NM_000374.5	P1

Frequencies

GnomAD3 genomes AF: 0.00 AC: 278 AN: 141466 Hom.: 0 Cov.: 32 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.: 0 Cov.: 41 AF XY: 0.180 AC XY: 76742 AN XY: 426990

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.: 0 Cov.: 32 AF XY: 0.00218 AC XY: 150 AN XY: 68718

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: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

UROD-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Aug 08, 2023

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	14
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

Other links and lift over

dbSNP: rs1569959434; hg19: chr1-45478569;