1-45012897-T-G

Variant names:

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

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_000374.5(UROD):​c.21-10T>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000358 in 839,118 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000036 (0 hom.)
• Consequence: UROD NM_000374.5 intron
• Scores: Splicing: ADA: 0.6884
• Clinical Significance: Not reported in ClinVar
• 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: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.73).

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>G		intron	N/A	NP_000365.3
	UROD	NR_036510.2		n.73T>G		non_coding_transcript_exon	Exon 2 of 10
	UROD	NR_158184.1		n.73T>G		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>G		intron	N/A	ENSP00000246337.4	P06132
	UROD	ENST00000461035.5	TSL:1	n.115T>G		non_coding_transcript_exon	Exon 2 of 4
	UROD	ENST00000651476.1		c.-95T>G		5_prime_UTR	Exon 2 of 10	ENSP00000498668.1	A0A494C0Q8

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000358 AC: 3 AN: 839118 Hom.: 0 Cov.: 41 AF XY: 0.00000694 AC XY: 3 AN XY: 432188

African (AFR) AF: 0.00 AC: 0 AN: 19454

American (AMR) AF: 0.00 AC: 0 AN: 38618

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 16998

East Asian (EAS) AF: 0.00 AC: 0 AN: 20178

South Asian (SAS) AF: 0.00 AC: 0 AN: 75328

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 37082

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3984

European-Non Finnish (NFE) AF: 0.00000337 AC: 2 AN: 593336

Other (OTH) AF: 0.0000293 AC: 1 AN: 34140

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.73
CADD	Benign	13
DANN	Benign	0.69
PhyloP100		0.45
PromoterAI		0.12	Neutral

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.69
dbscSNV1_RF	Benign	0.70
SpliceAI score (max)		0.37		Details are displayed if max score is > 0.2
DS_AL_spliceai		0.37		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;