Genetic Variant NM_000375.3:c.561+129C>G (chr10-125795974-G-C) – ACMG Classification: Benign (-14 pts)

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_StrongBP6_ModerateBA1

The NM_000375.3(UROS):c.561+129C>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.431 in 832,988 control chromosomes in the GnomAD database, including 79,252 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

Frequency

Genomes: 𝑓 0.43 ( 14207 hom., cov: 32)

Exomes 𝑓: 0.43 ( 65045 hom. )

Consequence

UROS
NM_000375.3 intron

Scores

Clinical Significance

Benign criteria provided, single submitter B:1

Conservation

PhyloP100: 0.0790

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 -14 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.84).

BP6

Variant 10-125795974-G-C is Benign according to our data. Variant chr10-125795974-G-C is described in ClinVar as Benign. ClinVar VariationId is 1265038.Status of the report is criteria_provided_single_submitter, 1 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+129C>G	intron	N/A	NP_000366.1	A0A0S2Z4T8
UROS	NM_001324036.2		c.561+129C>G	intron	N/A	NP_001310965.1	A0A3B3ISM6
UROS	NM_001324037.2		c.480+129C>G	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+129C>G	intron	N/A	ENSP00000357787.4	P10746
UROS	ENST00000368786.5	TSL:1	c.561+129C>G	intron	N/A	ENSP00000357775.1	P10746
UROS	ENST00000940865.1		c.660+129C>G	intron	N/A	ENSP00000610924.1

Frequencies

GnomAD3 genomes

AF:

0.429

AC:

65134

AN:

151886

Hom.:

14192

Cov.:

show subpopulations

Gnomad AFR

AF:

0.429

Gnomad AMI

AF:

0.538

Gnomad AMR

AF:

0.333

Gnomad ASJ

AF:

0.389

Gnomad EAS

AF:

0.290

Gnomad SAS

AF:

0.414

Gnomad FIN

AF:

0.429

Gnomad MID

AF:

0.310

Gnomad NFE

AF:

0.463

Gnomad OTH

AF:

0.425

GnomAD4 exome

AF:

0.431

AC:

293678

AN:

680984

Hom.:

65045

AF XY:

0.432

AC XY:

157418

AN XY:

364206

show subpopulations

African (AFR)

AF:

0.425

AC:

7858

AN:

18476

American (AMR)

AF:

0.246

AC:

10567

AN:

43024

Ashkenazi Jewish (ASJ)

AF:

0.388

AC:

8048

AN:

20758

East Asian (EAS)

AF:

0.313

AC:

11178

AN:

35756

South Asian (SAS)

AF:

0.414

AC:

28797

AN:

69538

European-Finnish (FIN)

AF:

0.424

AC:

21995

AN:

51912

Middle Eastern (MID)

AF:

0.339

AC:

884

AN:

2606

European-Non Finnish (NFE)

AF:

0.469

AC:

189871

AN:

404548

Other (OTH)

AF:

0.421

AC:

14480

AN:

34366

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.491

Heterozygous variant carriers

7834

15668

23502

31336

39170

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

2188

4376

6564

8752

10940

<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:

65180

AN:

152004

Hom.:

14207

Cov.:

AF XY:

0.423

AC XY:

31414

AN XY:

74284

show subpopulations

African (AFR)

AF:

0.429

AC:

17758

AN:

41426

American (AMR)

AF:

0.332

AC:

5073

AN:

15264

Ashkenazi Jewish (ASJ)

AF:

0.389

AC:

1350

AN:

3472

East Asian (EAS)

AF:

0.290

AC:

1500

AN:

5164

South Asian (SAS)

AF:

0.414

AC:

1994

AN:

4812

European-Finnish (FIN)

AF:

0.429

AC:

4531

AN:

10558

Middle Eastern (MID)

AF:

0.303

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.463

AC:

31491

AN:

67992

Other (OTH)

AF:

0.428

AC:

903

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

1932

3865

5797

7730

9662

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:

0.456

Hom.:

1929

Bravo

AF:

0.420

Asia WGS

AF:

0.367

AC:

1280

AN:

3478

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.84

CADD

Benign

2.2

(source)

DANN

Benign

0.82

PhyloP100

0.079

PromoterAI

-0.027

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

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