chr10-125788915-G-C

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 4P and 10B. PM1PM2BP4_StrongBP6_ModerateBS1

The NM_000375.3(UROS):ā€‹c.751C>Gā€‹(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 (ā˜…).

Frequency

Genomes: š‘“ 0.00053 ( 0 hom., cov: 33)
Exomes š‘“: 0.000044 ( 0 hom. )

Consequence

UROS
NM_000375.3 missense

Scores

4
8
7

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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -6 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_single_submitter, 1 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
UROSNM_000375.3 linkuse as main transcriptc.751C>G p.Leu251Val missense_variant 10/10 ENST00000368797.10

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
UROSENST00000368797.10 linkuse as main transcriptc.751C>G p.Leu251Val missense_variant 10/101 NM_000375.3 P1

Frequencies

GnomAD3 genomes
AF:
0.000532
AC:
81
AN:
152248
Hom.:
0
Cov.:
33
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:
34
AN:
234968
Hom.:
0
AF XY:
0.0000861
AC XY:
11
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:
64
AN:
1455446
Hom.:
0
Cov.:
30
AF XY:
0.0000304
AC XY:
22
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:
81
AN:
152366
Hom.:
0
Cov.:
33
AF XY:
0.000617
AC XY:
46
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.:
0
Bravo
AF:
0.000586
ESP6500AA
AF:
0.00159
AC:
7
ESP6500EA
AF:
0.00
AC:
0
ExAC
AF:
0.000149
AC:
18

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 submitterclinical testingInvitaeDec 28, 2023- -
UROS-related disorder Benign:1
Likely benign, criteria provided, single submitterclinical testingPreventionGenetics, part of Exact SciencesMar 04, 2023This 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
T
BayesDel_noAF
Pathogenic
0.21
CADD
Uncertain
24
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
D
LIST_S2
Uncertain
0.87
.;.;D;D;T
M_CAP
Uncertain
0.24
D
MetaRNN
Benign
0.043
T;T;T;T;T
MetaSVM
Pathogenic
0.87
D
MutationAssessor
Benign
1.5
L;L;L;.;.
MutationTaster
Benign
1.0
D;D
PrimateAI
Benign
0.44
T
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
T
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.

Other links and lift over

dbSNP: rs142834767; hg19: chr10-127477484; API