10-125795974-G-T

Variant names:

• chr10-125795974-G-T
• rs2281956
• NM_000375.3:c.561+129C>A

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.561+129C>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000044 in 682,012 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: 0.0000044 (0 hom.)
• Consequence: UROS NM_000375.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0790
• 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=-0.81).

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.561+129C>A		intron	N/A	NP_000366.1	A0A0S2Z4T8
	UROS	NM_001324036.2		c.561+129C>A		intron	N/A	NP_001310965.1	A0A3B3ISM6
	UROS	NM_001324037.2		c.480+129C>A		intron	N/A	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.561+129C>A		intron	N/A	ENSP00000357787.4	P10746
	UROS	ENST00000368786.5	TSL:1	c.561+129C>A		intron	N/A	ENSP00000357775.1	P10746
	UROS	ENST00000940865.1		c.660+129C>A		intron	N/A	ENSP00000610924.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000440 AC: 3 AN: 682012 Hom.: 0 AF XY: 0.00000274 AC XY: 1 AN XY: 364770

African (AFR) AF: 0.00 AC: 0 AN: 18500

American (AMR) AF: 0.00 AC: 0 AN: 43072

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 20796

East Asian (EAS) AF: 0.00 AC: 0 AN: 35786

South Asian (SAS) AF: 0.00 AC: 0 AN: 69616

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52014

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2614

European-Non Finnish (NFE) AF: 0.00000740 AC: 3 AN: 405196

Other (OTH) AF: 0.00 AC: 0 AN: 34418

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	2.1
DANN	Benign	0.87
PhyloP100		0.079
PromoterAI		-0.028	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs2281956; hg19: chr10-127484543;