1-45014835-CGG-GGT

Variant names:

• chr1-45014835-CGG-GGT
• NM_000374.5:c.874_875+1delCGGinsGGT
• UROD p.Arg292Gly

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PVS1_Moderate PP2

The NM_000374.5(UROD):​c.874_875+1delCGGinsGGT​(p.Arg292Gly) variant causes a splice donor, missense, splice region, intron change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. It is difficult to determine the true allele frequency of this variant because it is of type MNV, and the frequency of such variant types in population databases may be underestimated and unreliable. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Pathogenic in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R292W) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 33)
• Consequence: UROD NM_000374.5 splice_donor, missense, splice_region, intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.41
• 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 3 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.09148551 fraction of the gene. Cryptic splice site detected, with MaxEntScore 7.1, offset of 15, new splice context is: aggGTgagg. Cryptic site results in inframe change. If cryptic site found is not functional and variant results in exon loss, it results in frameshift change.
• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 14 curated pathogenic missense variants (we use a threshold of 10). The gene has 4 curated benign missense variants. Gene score misZ: 1.1116 (below the threshold of 3.09). Trascript score misZ: 1.9283 (below the threshold of 3.09). GenCC associations: The gene is linked to hepatoerythropoietic porphyria, familial porphyria cutanea tarda, UROD-related inherited porphyria.

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.874_875+1delCGGinsGGT	p.Arg292Gly	splice_donor missense splice_region intron	N/A	NP_000365.3
	UROD	NR_036510.2		n.936_937+1delCGGinsGGT		splice_donor splice_region intron non_coding_transcript_exon	Exon 8 of 10
	UROD	NR_158184.1		n.955_956+1delCGGinsGGT		splice_donor splice_region intron non_coding_transcript_exon	Exon 8 of 10

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	UROD	ENST00000246337.9	TSL:1 MANE Select	c.874_875+1delCGGinsGGT	p.Arg292Gly	splice_donor missense splice_region intron	N/A	ENSP00000246337.4	P06132
	UROD	ENST00000894914.1		c.898_899+1delCGGinsGGT	p.Arg300Gly	splice_donor missense splice_region intron	N/A	ENSP00000564973.1
	UROD	ENST00000894916.1		c.889_890+1delCGGinsGGT	p.Arg297Gly	splice_donor missense splice_region intron	N/A	ENSP00000564975.1

Frequencies

GnomAD3 genomes Cov.: 33

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		7.4

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

hg19: chr1-45480507;