NM_000375.3:c.-26-183G>A

Variant names:

• chr10-125816708-C-T
• rs397515349
• NM_000375.3:c.-26-183G>A

Variant summary

Our verdict is Likely pathogenic. The variant received 7 ACMG points: 8P and 1B. PS3 PM2 PP5_Moderate BP4

The NM_000375.3(UROS):​c.-26-183G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000841 in 475,390 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★). ClinVar reports functional evidence for this variant: "SCV002242575: Experimental studies have shown that this variant affects UROS function (PMID:27859603).".

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000084 (0 hom.)
• Consequence: UROS NM_000375.3 intron
• Clinical Significance: Pathogenic criteria provided, single submitter P:3
• Conservation: PhyloP100: 0.198
• Publications: 2 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_pathogenic. The variant received 7 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV002242575: Experimental studies have shown that this variant affects UROS function (PMID: 27859603).
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 10-125816708-C-T is Pathogenic according to our data. Variant chr10-125816708-C-T is described in ClinVar as Pathogenic. ClinVar VariationId is 3763.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.25). . Strength limited to SUPPORTING due to the PP5.

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.-26-183G>A		intron	N/A	NP_000366.1	A0A0S2Z4T8
	UROS	NM_001324036.2		c.-26-183G>A		intron	N/A	NP_001310965.1	A0A3B3ISM6
	UROS	NM_001324037.2		c.-26-183G>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.-26-183G>A		intron	N/A	ENSP00000357787.4	P10746
	UROS	ENST00000940865.1		c.-26-183G>A		intron	N/A	ENSP00000610924.1
	UROS	ENST00000879953.1		c.-26-183G>A		intron	N/A	ENSP00000550012.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000841 AC: 4 AN: 475390 Hom.: 0 AF XY: 0.0000119 AC XY: 3 AN XY: 252252

African (AFR) AF: 0.00 AC: 0 AN: 13044

American (AMR) AF: 0.00 AC: 0 AN: 22190

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 14654

East Asian (EAS) AF: 0.00 AC: 0 AN: 31308

South Asian (SAS) AF: 0.00 AC: 0 AN: 47484

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 30010

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2126

European-Non Finnish (NFE) AF: 0.0000139 AC: 4 AN: 287550

Other (OTH) AF: 0.00 AC: 0 AN: 27024

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
2	-	-	Cutaneous porphyria (2)
1	-	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.25
CADD	Benign	15
DANN	Benign	0.85
PhyloP100		0.20
PromoterAI		-0.060	Neutral
Mutation Taster		=27/73	disease causing (ClinVar)

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: rs397515349; hg19: chr10-127505277;