10-125816708-C-T

Variant names:

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

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 4P and 1B. 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 (★).

• 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: Genomics England PanelApp, Labcorp Genetics (formerly Invitae), G2P, Orphanet

ACMG classification

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

• 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 id 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
UROS	NM_000375.3	c.-26-183G>A		intron_variant	Intron 1 of 9	ENST00000368797.10	NP_000366.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
UROS	ENST00000368797.10	c.-26-183G>A		intron_variant	Intron 1 of 9	1	NM_000375.3	ENSP00000357787.4

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

Significance: Pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, single submitter

Submissions by phenotype

Cutaneous porphyria Pathogenic:2

Apr 07, 2016

GeneReviews

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Mar 01, 2001

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

not provided Pathogenic:1

Dec 02, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change falls in intron 1 of the UROS gene. It does not directly change the encoded amino acid sequence of the UROS protein. This variant is not present in population databases (gnomAD no frequency). This variant has been observed in individuals with congenital erythropoietic porphyria (PMID: 11254675, 16365260, 27859603). It has also been observed to segregate with disease in related individuals. This variant is also known as -76G>A or 1-209G>A. ClinVar contains an entry for this variant (Variation ID: 3763). Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. Experimental studies have shown that this variant affects UROS function (PMID: 27859603). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant is not likely to affect RNA splicing. For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

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;