10-125788915-G-C

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 4P and 16B. PM1PM2BP4_StrongBP6_Very_StrongBS1

The NM_000375.3(UROS):c.751C>G(p.Leu251Val) variant causes a missense change. The variant allele was found at a frequency of 0.0000902 in 1,607,812 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.00053 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000044 ( 0 hom. )

Consequence

UROS
NM_000375.3 missense

Scores

Clinical Significance

Likely benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: 4.19

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -12 ACMG points.

PM1

In a chain Uroporphyrinogen-III synthase (size 264) in uniprot entity HEM4_HUMAN there are 25 pathogenic changes around while only 9 benign (74%) in NM_000375.3

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.043350726).

BP6

Variant 10-125788915-G-C is Benign according to our data. Variant chr10-125788915-G-C is described in ClinVar as [Likely_benign]. Clinvar id is 747073.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.000532 (81/152366) while in subpopulation AFR AF= 0.00195 (81/41598). AF 95% confidence interval is 0.0016. There are 0 homozygotes in gnomad4. There are 46 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
UROS	NM_000375.3 linkuse as main transcript	c.751C>G	p.Leu251Val	missense_variant	10/10	ENST00000368797.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
UROS	ENST00000368797.10 linkuse as main transcript	c.751C>G	p.Leu251Val	missense_variant	10/10	1	NM_000375.3	P1

Frequencies

GnomAD3 genomes

AF:

0.000532

AC:

AN:

152248

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00195

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000145

AC:

AN:

234968

Hom.:

AF XY:

0.0000861

AC XY:

AN XY:

127752

show subpopulations

Gnomad AFR exome

AF:

0.00226

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000952

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000440

AC:

AN:

1455446

Hom.:

Cov.:

AF XY:

0.0000304

AC XY:

AN XY:

723514

show subpopulations

Gnomad4 AFR exome

AF:

0.00146

Gnomad4 AMR exome

AF:

0.0000457

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

9.01e-7

Gnomad4 OTH exome

AF:

0.000200

GnomAD4 genome

AF:

0.000532

AC:

AN:

152366

Hom.:

Cov.:

AF XY:

0.000617

AC XY:

AN XY:

74518

show subpopulations

Gnomad4 AFR

AF:

0.00195

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000298

Hom.:

Bravo

AF:

0.000586

ESP6500AA

AF:

0.00159

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.000149

AC:

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Dec 28, 2023

- -

UROS-related disorder

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Mar 04, 2023

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.15

BayesDel_addAF

Benign

-0.0063

BayesDel_noAF

Pathogenic

0.21

Cadd

Uncertain

Dann

Uncertain

0.99

DEOGEN2

Uncertain

0.68

D;D;D;.;.

Eigen

Uncertain

0.46

Eigen_PC

Uncertain

0.39

FATHMM_MKL

Uncertain

0.90

M_CAP

Uncertain

0.24

MetaRNN

Benign

0.043

T;T;T;T;T

MetaSVM

Pathogenic

0.87

MutationAssessor

Benign

1.5

L;L;L;.;.

MutationTaster

Benign

1.0

D;D

PrimateAI

Benign

0.44

PROVEAN

Benign

-1.9

N;.;N;.;.

REVEL

Pathogenic

0.68

Sift

Pathogenic

0.0

D;.;D;.;.

Sift4G

Uncertain

0.048

D;.;D;.;.

Polyphen

1.0

D;D;D;.;.

Vest4

0.61

MVP

0.87

MPC

0.47

ClinPred

0.16

GERP RS

4.0

Varity_R

0.81

gMVP

0.73

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