rs3740179

Variant names:

• chr10-125795004-G-A
• rs3740179
• NM_000375.3:c.562-26C>T

Variant summary

Our verdict is Benign. The variant received -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
• Publications: 28 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: Benign. The variant received -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 CliVar as Benign. Clinvar id is 1266364.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-125795004-G-A is described in CliVar as Benign. Clinvar id is 1266364.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-125795004-G-A is described in CliVar as Benign. Clinvar id is 1266364.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-125795004-G-A is described in CliVar as Benign. Clinvar id is 1266364.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-125795004-G-A is described in CliVar as Benign. Clinvar id is 1266364.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-125795004-G-A is described in CliVar as Benign. Clinvar id is 1266364.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-125795004-G-A is described in CliVar as Benign. Clinvar id is 1266364.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-125795004-G-A is described in CliVar as Benign. Clinvar id is 1266364.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-125795004-G-A is described in CliVar as Benign. Clinvar id is 1266364.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-125795004-G-A is described in CliVar as Benign. Clinvar id is 1266364.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-125795004-G-A is described in CliVar as Benign. Clinvar id is 1266364.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-125795004-G-A is described in CliVar as Benign. Clinvar id is 1266364.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-125795004-G-A is described in CliVar as Benign. Clinvar id is 1266364.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-125795004-G-A is described in CliVar as Benign. Clinvar id is 1266364.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-125795004-G-A is described in CliVar as Benign. Clinvar id is 1266364.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-125795004-G-A is described in CliVar as Benign. Clinvar id is 1266364.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-125795004-G-A is described in CliVar as Benign. Clinvar id is 1266364.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-125795004-G-A is described in CliVar as Benign. Clinvar id is 1266364.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-125795004-G-A is described in CliVar as Benign. Clinvar id is 1266364.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-125795004-G-A is described in CliVar as Benign. Clinvar id is 1266364.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-125795004-G-A is described in CliVar as Benign. Clinvar id is 1266364.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-125795004-G-A is described in CliVar as Benign. Clinvar id is 1266364.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-125795004-G-A is described in CliVar as Benign. Clinvar id is 1266364.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-125795004-G-A is described in CliVar as Benign. Clinvar id is 1266364.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-125795004-G-A is described in CliVar as Benign. Clinvar id is 1266364.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-125795004-G-A is described in CliVar as Benign. Clinvar id is 1266364.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-125795004-G-A is described in CliVar as Benign. Clinvar id is 1266364.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-125795004-G-A is described in CliVar as Benign. Clinvar id is 1266364.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-125795004-G-A is described in CliVar as Benign. Clinvar id is 1266364.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-125795004-G-A is described in CliVar as Benign. Clinvar id is 1266364.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-125795004-G-A is described in CliVar as Benign. Clinvar id is 1266364.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-125795004-G-A is described in CliVar as Benign. Clinvar id is 1266364.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-125795004-G-A is described in CliVar as Benign. Clinvar id is 1266364.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-125795004-G-A is described in CliVar as Benign. Clinvar id is 1266364.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-125795004-G-A is described in CliVar as Benign. Clinvar id is 1266364.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-125795004-G-A is described in CliVar as Benign. Clinvar id is 1266364.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-125795004-G-A is described in CliVar as Benign. Clinvar id is 1266364.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-125795004-G-A is described in CliVar as Benign. Clinvar id is 1266364.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-125795004-G-A is described in CliVar 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 rank	MANE	Protein	UniProt
UROS	NM_000375.3	c.562-26C>T		intron_variant	Intron 8 of 9	ENST00000368797.10	NP_000366.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
UROS	ENST00000368797.10	c.562-26C>T		intron_variant	Intron 8 of 9	1	NM_000375.3	ENSP00000357787.4

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

GnomAD2 exomes AF: 0.400 AC: 100478 AN: 250906 AF XY: 0.407

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 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

African (AFR) AF: 0.425 AC: 13996 AN: 32916

American (AMR) AF: 0.248 AC: 11073 AN: 44668

Ashkenazi Jewish (ASJ) AF: 0.382 AC: 9920 AN: 25974

East Asian (EAS) AF: 0.321 AC: 12669 AN: 39516

South Asian (SAS) AF: 0.424 AC: 36297 AN: 85702

European-Finnish (FIN) AF: 0.425 AC: 22677 AN: 53338

Middle Eastern (MID) AF: 0.328 AC: 1876 AN: 5712

European-Non Finnish (NFE) AF: 0.469 AC: 510711 AN: 1089674

Other (OTH) AF: 0.429 AC: 25572 AN: 59612

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

African (AFR) AF: 0.429 AC: 17787 AN: 41508

American (AMR) AF: 0.332 AC: 5078 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.382 AC: 1326 AN: 3472

East Asian (EAS) AF: 0.301 AC: 1552 AN: 5160

South Asian (SAS) AF: 0.424 AC: 2042 AN: 4814

European-Finnish (FIN) AF: 0.429 AC: 4534 AN: 10572

Middle Eastern (MID) AF: 0.303 AC: 89 AN: 294

European-Non Finnish (NFE) AF: 0.463 AC: 31480 AN: 67964

Other (OTH) AF: 0.427 AC: 900 AN: 2110

Alfa AF: 0.442 Hom.: 42963

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

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Nov 12, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Cutaneous porphyria Benign:1

Dec 05, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	0.85
DANN	Benign	0.69
PhyloP100		-0.35
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Mutation Taster		=100/0	polymorphism (auto)

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