rs3740179

Positions:

• chr10-125795004-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000375.3(UROS):​c.562-26C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.447 in 1,589,188 control chromosomes in the GnomAD database, including 161,003 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.43 (14234 hom., cov: 32)
  • Exomes 𝑓: 0.45 (146769 hom.)
• Consequence: UROS NM_000375.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.352

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]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.88).
• BP6: Variant 10-125795004-G-A is Benign according to our data. Variant chr10-125795004-G-A is described in ClinVar as [Benign]. Clinvar id is 1266364.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.459 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
UROS	NM_000375.3	c.562-26C>T		intron_variant		ENST00000368797.10	NP_000366.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
UROS	ENST00000368797.10	c.562-26C>T		intron_variant		1	NM_000375.3	ENSP00000357787	P1

Frequencies

GnomAD3 genomes AF: 0.429 AC: 65234 AN: 151958 Hom.: 14220 Cov.: 32

Gnomad AFR AF: 0.429

Gnomad AMI AF: 0.541

Gnomad AMR AF: 0.333

Gnomad ASJ AF: 0.382

Gnomad EAS AF: 0.300

Gnomad SAS AF: 0.424

Gnomad FIN AF: 0.429

Gnomad MID AF: 0.310

Gnomad NFE AF: 0.463

Gnomad OTH AF: 0.424

GnomAD3 exomes AF: 0.400 AC: 100478 AN: 250906 Hom.: 21194 AF XY: 0.407 AC XY: 55141 AN XY: 135622

Gnomad AFR exome AF: 0.431

Gnomad AMR exome AF: 0.239

Gnomad ASJ exome AF: 0.374

Gnomad EAS exome AF: 0.271

Gnomad SAS exome AF: 0.425

Gnomad FIN exome AF: 0.419

Gnomad NFE exome AF: 0.458

Gnomad OTH exome AF: 0.400

GnomAD4 exome AF: 0.449 AC: 644791 AN: 1437112 Hom.: 146769 Cov.: 27 AF XY: 0.448 AC XY: 321367 AN XY: 716656

Gnomad4 AFR exome AF: 0.425

Gnomad4 AMR exome AF: 0.248

Gnomad4 ASJ exome AF: 0.382

Gnomad4 EAS exome AF: 0.321

Gnomad4 SAS exome AF: 0.424

Gnomad4 FIN exome AF: 0.425

Gnomad4 NFE exome AF: 0.469

Gnomad4 OTH exome AF: 0.429

GnomAD4 genome AF: 0.429 AC: 65279 AN: 152076 Hom.: 14234 Cov.: 32 AF XY: 0.423 AC XY: 31479 AN XY: 74340

Gnomad4 AFR AF: 0.429

Gnomad4 AMR AF: 0.332

Gnomad4 ASJ AF: 0.382

Gnomad4 EAS AF: 0.301

Gnomad4 SAS AF: 0.424

Gnomad4 FIN AF: 0.429

Gnomad4 NFE AF: 0.463

Gnomad4 OTH AF: 0.427

Alfa AF: 0.443 Hom.: 26437

Bravo AF: 0.419

Asia WGS AF: 0.372 AC: 1297 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 12, 2018	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Cutaneous porphyria Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Dec 05, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	0.85
DANN	Benign	0.69
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0

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

Publications

LitVar

Other links and lift over

dbSNP: rs3740179; hg19: chr10-127483573; COSMIC: COSV64229637;