Genetic Variant UROS:c.562-26C>T (chr10-125795004-G-A) – ACMG Classification: Benign (-20 pts)

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

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

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: -0.352

Variant links:

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 links:

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ACMG classification

Classification was made for transcript

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 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 rank	MANE	Protein	UniProt
UROS	NM_000375.3 link	c.562-26C>T		intron_variant	Intron 8 of 9	ENST00000368797.10	NP_000366.1	P10746A0A0S2Z4T8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
UROS	ENST00000368797.10 link	c.562-26C>T		intron_variant	Intron 8 of 9	1	NM_000375.3	ENSP00000357787.4		P10746

Frequencies

GnomAD3 genomes

AF:

0.429

AC:

65234

AN:

151958

Hom.:

14220

Cov.:

show subpopulations

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

show subpopulations

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.:

AF XY:

0.448

AC XY:

321367

AN XY:

716656

show subpopulations

Gnomad4 AFR exome

AF:

0.425

AC:

13996

AN:

32916

Gnomad4 AMR exome

AF:

0.248

AC:

11073

AN:

44668

Gnomad4 ASJ exome

AF:

0.382

AC:

9920

AN:

25974

Gnomad4 EAS exome

AF:

0.321

AC:

12669

AN:

39516

Gnomad4 SAS exome

AF:

0.424

AC:

36297

AN:

85702

Gnomad4 FIN exome

AF:

0.425

AC:

22677

AN:

53338

Gnomad4 NFE exome

AF:

0.469

AC:

510711

AN:

1089674

Gnomad4 Remaining exome

AF:

0.429

AC:

25572

AN:

59612

Heterozygous variant carriers

16697

33393

50090

66786

83483

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Exome Het

Exome Hom

Variant carriers

14914

29828

44742

59656

74570

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.429

AC:

65279

AN:

152076

Hom.:

14234

Cov.:

AF XY:

0.423

AC XY:

31479

AN XY:

74340

show subpopulations

Gnomad4 AFR

AF:

0.429

AC:

0.42852

AN:

0.42852

Gnomad4 AMR

AF:

0.332

AC:

0.33246

AN:

0.33246

Gnomad4 ASJ

AF:

0.382

AC:

0.381912

AN:

0.381912

Gnomad4 EAS

AF:

0.301

AC:

0.300775

AN:

0.300775

Gnomad4 SAS

AF:

0.424

AC:

0.424179

AN:

0.424179

Gnomad4 FIN

AF:

0.429

AC:

0.428869

AN:

0.428869

Gnomad4 NFE

AF:

0.463

AC:

0.463186

AN:

0.463186

Gnomad4 OTH

AF:

0.427

AC:

0.42654

AN:

0.42654

Heterozygous variant carriers

1881

3761

5642

7522

9403

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Genome Het

Genome Hom

Variant carriers

606

1212

1818

2424

3030

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

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

LINK: link

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

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over