10-125823221-G-T

Position:

• chr10-125823221-G-T

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.-219C>A variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.433 in 221,424 control chromosomes in the GnomAD database, including 21,324 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.42 (13475 hom., cov: 35)
  • Exomes 𝑓: 0.47 (7849 hom.)
• Consequence: UROS NM_000375.3 5_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3 O:1
• Conservation: PhyloP100: -2.01

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 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.87).
• BP6: Variant 10-125823221-G-T is Benign according to our data. Variant chr10-125823221-G-T is described in ClinVar as [Benign]. Clinvar id is 225268.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.462 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
UROS	NM_000375.3	c.-219C>A		5_prime_UTR_variant	1/10	ENST00000368797.10	NP_000366.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
UROS	ENST00000368797.10	c.-219C>A		5_prime_UTR_variant	1/10	1	NM_000375.3	ENSP00000357787.4

Frequencies

GnomAD3 genomes AF: 0.416 AC: 63184 AN: 152020 Hom.: 13460 Cov.: 35

Gnomad AFR AF: 0.377

Gnomad AMI AF: 0.537

Gnomad AMR AF: 0.329

Gnomad ASJ AF: 0.390

Gnomad EAS AF: 0.292

Gnomad SAS AF: 0.411

Gnomad FIN AF: 0.428

Gnomad MID AF: 0.307

Gnomad NFE AF: 0.466

Gnomad OTH AF: 0.418

GnomAD4 exome AF: 0.470 AC: 32543 AN: 69286 Hom.: 7849 Cov.: 0 AF XY: 0.469 AC XY: 16698 AN XY: 35638

Gnomad4 AFR exome AF: 0.382

Gnomad4 AMR exome AF: 0.338

Gnomad4 ASJ exome AF: 0.419

Gnomad4 EAS exome AF: 0.356

Gnomad4 SAS exome AF: 0.477

Gnomad4 FIN exome AF: 0.469

Gnomad4 NFE exome AF: 0.500

Gnomad4 OTH exome AF: 0.434

GnomAD4 genome AF: 0.416 AC: 63229 AN: 152138 Hom.: 13475 Cov.: 35 AF XY: 0.411 AC XY: 30540 AN XY: 74392

Gnomad4 AFR AF: 0.377

Gnomad4 AMR AF: 0.329

Gnomad4 ASJ AF: 0.390

Gnomad4 EAS AF: 0.292

Gnomad4 SAS AF: 0.412

Gnomad4 FIN AF: 0.428

Gnomad4 NFE AF: 0.466

Gnomad4 OTH AF: 0.421

Alfa AF: 0.338 Hom.: 952

Bravo AF: 0.404

Asia WGS AF: 0.363 AC: 1266 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Cutaneous porphyria Benign:1 Other:1

not provided, no classification provided	literature only	GeneReviews	-	Pathogenic variants in the erythroid-specific promoter region 2 -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Mendelics

May 04, 2022

- -

not provided Benign:1

Benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

-

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	0.42
DANN	Benign	0.79
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: rs4385801; hg19: chr10-127511790;