10-125815035-T-C

Variant names:

• chr10-125815035-T-C
• rs121908018
• NM_000375.3:c.243A>G

Variant summary

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

The NM_000375.3(UROS):​c.243A>G​(p.Glu81Glu) variant causes a splice region, synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,838 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: UROS NM_000375.3 splice_region, synonymous
• Scores: Splicing: ADA: 0.4828
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.78
• Publications: 0 publications found

Genes affected

UROS (HGNC:12592): (uroporphyrinogen III synthase) The protein encoded by this gene catalyzes the fourth step of porphyrin biosynthesis in the heme biosynthetic pathway. Defects in this gene cause congenital erythropoietic porphyria (Gunther's disease). [provided by RefSeq, Jul 2008]

UROS Gene-Disease associations (from GenCC):

• cutaneous porphyria

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: ClinGen, Genomics England PanelApp, Labcorp Genetics (formerly Invitae), G2P, 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=-0.48).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000375.3. 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
	UROS	NM_000375.3	MANE Select	c.243A>G	p.Glu81Glu	splice_region synonymous	Exon 4 of 10	NP_000366.1	A0A0S2Z4T8
	UROS	NM_001324036.2		c.243A>G	p.Glu81Glu	splice_region synonymous	Exon 4 of 11	NP_001310965.1	A0A3B3ISM6
	UROS	NM_001324037.2		c.243A>G	p.Glu81Glu	splice_region synonymous	Exon 4 of 10	NP_001310966.1	A0A3B3ITJ2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	UROS	ENST00000368797.10	TSL:1 MANE Select	c.243A>G	p.Glu81Glu	splice_region synonymous	Exon 4 of 10	ENSP00000357787.4	P10746
	UROS	ENST00000368786.5	TSL:1	c.243A>G	p.Glu81Glu	splice_region synonymous	Exon 3 of 9	ENSP00000357775.1	P10746
	UROS	ENST00000940865.1		c.243A>G	p.Glu81Glu	synonymous	Exon 4 of 11	ENSP00000610924.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461838 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 727216

African (AFR) AF: 0.00 AC: 0 AN: 33478

American (AMR) AF: 0.00 AC: 0 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26130

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86254

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53414

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1111986

Other (OTH) AF: 0.00 AC: 0 AN: 60392

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.48
CADD	Benign	19
DANN	Benign	0.78
PhyloP100		2.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.48
dbscSNV1_RF	Benign	0.63
SpliceAI score (max)		0.87		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.87		Position offset: -1

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

Other links and lift over

dbSNP: rs121908018; hg19: chr10-127503604;