NM_000374.5:c.21-10T>A

Variant names:

• chr1-45012897-T-A
• rs1569959434
• NM_000374.5:c.21-10T>A

Variant summary

Our verdict is Uncertain significance. The variant received 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:1 B:1
• Conservation: PhyloP100: 0.445
• Publications: 0 publications found

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 Gene-Disease associations (from GenCC):

• UROD-related inherited porphyria

  Inheritance: SD Classification: DEFINITIVE Submitted by: ClinGen, Ambry Genetics
• familial porphyria cutanea tarda

  Inheritance: AD, AR Classification: STRONG, SUPPORTIVE Submitted by: Genomics England PanelApp, Orphanet, Labcorp Genetics (formerly Invitae)
• hepatoerythropoietic porphyria

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF, max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000374.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	UROD	NM_000374.5	MANE Select	c.21-10T>A		intron	N/A	NP_000365.3
	UROD	NR_036510.2		n.73T>A		non_coding_transcript_exon	Exon 2 of 10
	UROD	NR_158184.1		n.73T>A		non_coding_transcript_exon	Exon 2 of 10

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	UROD	ENST00000246337.9	TSL:1 MANE Select	c.21-10T>A		intron	N/A	ENSP00000246337.4	P06132
	UROD	ENST00000461035.5	TSL:1	n.115T>A		non_coding_transcript_exon	Exon 2 of 4
	UROD	ENST00000651476.1		c.-95T>A		5_prime_UTR	Exon 2 of 10	ENSP00000498668.1	A0A494C0Q8

Frequencies

GnomAD3 genomes AF: 0.00197 AC: 278 AN: 141466 Hom.: 0 Cov.: 32

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

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.161 AC: 3089 AN: 19218

American (AMR) AF: 0.0244 AC: 940 AN: 38532

Ashkenazi Jewish (ASJ) AF: 0.111 AC: 1874 AN: 16824

East Asian (EAS) AF: 0.111 AC: 2223 AN: 19942

South Asian (SAS) AF: 0.0390 AC: 2928 AN: 75104

European-Finnish (FIN) AF: 0.0424 AC: 1563 AN: 36886

Middle Eastern (MID) AF: 0.102 AC: 405 AN: 3956

European-Non Finnish (NFE) AF: 0.244 AC: 142571 AN: 583972

Other (OTH) AF: 0.184 AC: 6190 AN: 33708

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

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

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00118 AC: 46 AN: 38856

American (AMR) AF: 0.00126 AC: 18 AN: 14342

Ashkenazi Jewish (ASJ) AF: 0.00271 AC: 9 AN: 3322

East Asian (EAS) AF: 0.00640 AC: 27 AN: 4216

South Asian (SAS) AF: 0.00545 AC: 22 AN: 4038

European-Finnish (FIN) AF: 0.00258 AC: 23 AN: 8914

Middle Eastern (MID) AF: 0.00360 AC: 1 AN: 278

European-Non Finnish (NFE) AF: 0.00198 AC: 128 AN: 64716

Other (OTH) AF: 0.00149 AC: 3 AN: 2012

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	UROD-related disorder (1)
-	1	-	UROD-related inherited porphyria (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.70
CADD	Benign	14
DANN	Benign	0.78
PhyloP100		0.45
PromoterAI		0.047	Neutral
Mutation Taster		=15/85	disease causing

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

Other links and lift over

dbSNP: rs1569959434; hg19: chr1-45478569;