dbSNP rs2281955: UROS:c.561+55G>C (chr10-125796048-C-G) – 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.561+55G>C 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 1,534,740 control chromosomes in the GnomAD database, including 155,769 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.43 ( 14212 hom., cov: 32)

Exomes 𝑓: 0.45 ( 141557 hom. )

Consequence

UROS
NM_000375.3 intron

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: -1.63

Publications

13 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 -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.96).

BP6

Variant 10-125796048-C-G is Benign according to our data. Variant chr10-125796048-C-G is described in ClinVar as Benign. ClinVar VariationId is 1257905.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.

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.561+55G>C	intron	N/A	NP_000366.1	A0A0S2Z4T8
UROS	NM_001324036.2		c.561+55G>C	intron	N/A	NP_001310965.1	A0A3B3ISM6
UROS	NM_001324037.2		c.480+55G>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.561+55G>C	intron	N/A	ENSP00000357787.4	P10746
UROS	ENST00000368786.5	TSL:1	c.561+55G>C	intron	N/A	ENSP00000357775.1	P10746
UROS	ENST00000940865.1		c.660+55G>C	intron	N/A	ENSP00000610924.1

Frequencies

GnomAD3 genomes

AF:

0.429

AC:

65181

AN:

151894

Hom.:

14196

Cov.:

show subpopulations

Gnomad AFR

AF:

0.427

Gnomad AMI

AF:

0.538

Gnomad AMR

AF:

0.334

Gnomad ASJ

AF:

0.390

Gnomad EAS

AF:

0.294

Gnomad SAS

AF:

0.424

Gnomad FIN

AF:

0.429

Gnomad MID

AF:

0.313

Gnomad NFE

AF:

0.463

Gnomad OTH

AF:

0.428

GnomAD4 exome

AF:

0.449

AC:

620885

AN:

1382728

Hom.:

141557

AF XY:

0.449

AC XY:

310876

AN XY:

692628

show subpopulations

African (AFR)

AF:

0.425

AC:

13504

AN:

31790

American (AMR)

AF:

0.248

AC:

11083

AN:

44624

Ashkenazi Jewish (ASJ)

AF:

0.390

AC:

9990

AN:

25646

East Asian (EAS)

AF:

0.306

AC:

12050

AN:

39320

South Asian (SAS)

AF:

0.424

AC:

35879

AN:

84696

European-Finnish (FIN)

AF:

0.427

AC:

22775

AN:

53352

Middle Eastern (MID)

AF:

0.336

AC:

1642

AN:

4888

European-Non Finnish (NFE)

AF:

0.470

AC:

489202

AN:

1040714

Other (OTH)

AF:

0.429

AC:

24760

AN:

57698

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

16981

33963

50944

67926

84907

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

14002

28004

42006

56008

70010

<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:

65227

AN:

152012

Hom.:

14212

Cov.:

AF XY:

0.423

AC XY:

31452

AN XY:

74286

show subpopulations

African (AFR)

AF:

0.427

AC:

17703

AN:

41446

American (AMR)

AF:

0.334

AC:

5096

AN:

15280

Ashkenazi Jewish (ASJ)

AF:

0.390

AC:

1354

AN:

3472

East Asian (EAS)

AF:

0.294

AC:

1516

AN:

5154

South Asian (SAS)

AF:

0.425

AC:

2044

AN:

4810

European-Finnish (FIN)

AF:

0.429

AC:

4535

AN:

10560

Middle Eastern (MID)

AF:

0.306

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.463

AC:

31492

AN:

67978

Other (OTH)

AF:

0.430

AC:

906

AN:

2106

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

1935

3870

5805

7740

9675

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:

0.447

Hom.:

1813

Bravo

AF:

0.419

Asia WGS

AF:

0.372

AC:

1294

AN:

3478

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (2)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.96

CADD

Benign

0.23

(source)

DANN

Benign

0.50

PhyloP100

-1.6

PromoterAI

-0.018

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

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