Genetic Variant UROS:c.476-497T>C (chr10-125796685-A-G) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_000375.3(UROS):c.476-497T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.456 in 729,002 control chromosomes in the GnomAD database, including 76,929 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.43 ( 14179 hom., cov: 32)

Exomes 𝑓: 0.46 ( 62750 hom. )

Consequence

UROS
NM_000375.3 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.148

Publications

17 publications found

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 Gene-Disease associations (from GenCC):

cutaneous porphyria
Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: ClinGen, Genomics England PanelApp, Labcorp Genetics (formerly Invitae), G2P, Orphanet

UROS links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.98).

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.458 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000375.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
UROS	NM_000375.3	MANE Select	c.476-497T>C	intron	N/A	NP_000366.1	A0A0S2Z4T8
UROS	NM_001324036.2		c.476-497T>C	intron	N/A	NP_001310965.1	A0A3B3ISM6
UROS	NM_001324037.2		c.395-497T>C	intron	N/A	NP_001310966.1	A0A3B3ITJ2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
UROS	ENST00000368797.10	TSL:1 MANE Select	c.476-497T>C	intron	N/A	ENSP00000357787.4	P10746
UROS	ENST00000368786.5	TSL:1	c.476-497T>C	intron	N/A	ENSP00000357775.1	P10746
UROS	ENST00000940865.1		c.575-497T>C	intron	N/A	ENSP00000610924.1

Frequencies

GnomAD3 genomes

AF:

0.429

AC:

65140

AN:

151900

Hom.:

14167

Cov.:

show subpopulations

Gnomad AFR

AF:

0.430

Gnomad AMI

AF:

0.525

Gnomad AMR

AF:

0.336

Gnomad ASJ

AF:

0.399

Gnomad EAS

AF:

0.293

Gnomad SAS

AF:

0.398

Gnomad FIN

AF:

0.432

Gnomad MID

AF:

0.291

Gnomad NFE

AF:

0.462

Gnomad OTH

AF:

0.427

GnomAD4 exome

AF:

0.464

AC:

267471

AN:

576984

Hom.:

62750

AF XY:

0.464

AC XY:

125299

AN XY:

270058

show subpopulations

African (AFR)

AF:

0.425

AC:

4475

AN:

10538

American (AMR)

AF:

0.275

AC:

179

AN:

652

Ashkenazi Jewish (ASJ)

AF:

0.408

AC:

1430

AN:

3502

East Asian (EAS)

AF:

0.277

AC:

664

AN:

2396

South Asian (SAS)

AF:

0.401

AC:

4539

AN:

11314

European-Finnish (FIN)

AF:

0.410

AC:

AN:

188

Middle Eastern (MID)

AF:

0.352

AC:

388

AN:

1102

European-Non Finnish (NFE)

AF:

0.468

AC:

247470

AN:

528422

Other (OTH)

AF:

0.437

AC:

8249

AN:

18870

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.506

Heterozygous variant carriers

6722

13445

20167

26890

33612

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

9968

19936

29904

39872

49840

<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:

65181

AN:

152018

Hom.:

14179

Cov.:

AF XY:

0.423

AC XY:

31407

AN XY:

74280

show subpopulations

African (AFR)

AF:

0.430

AC:

17815

AN:

41460

American (AMR)

AF:

0.336

AC:

5129

AN:

15284

Ashkenazi Jewish (ASJ)

AF:

0.399

AC:

1386

AN:

3470

East Asian (EAS)

AF:

0.293

AC:

1511

AN:

5152

South Asian (SAS)

AF:

0.398

AC:

1918

AN:

4816

European-Finnish (FIN)

AF:

0.432

AC:

4559

AN:

10560

Middle Eastern (MID)

AF:

0.282

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.462

AC:

31397

AN:

67962

Other (OTH)

AF:

0.429

AC:

904

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

1923

3846

5770

7693

9616

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

604

1208

1812

2416

3020

<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:

0.426

Hom.:

10431

Bravo

AF:

0.420

Asia WGS

AF:

0.363

AC:

1263

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.98

CADD

Benign

1.9

(source)

DANN

Benign

0.55

PhyloP100

-0.15

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over