chr10-125788915-G-C
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Variant summary
Our verdict is Likely benign. Variant got -6 ACMG points: 4P and 10B. PM1PM2BP4_StrongBP6_ModerateBS1
The NM_000375.3(UROS):āc.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
NM_000375.3 missense
Scores
4
8
7
Clinical Significance
Conservation
PhyloP100: 4.19
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]
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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 |
---|---|---|---|---|---|---|---|
UROS | NM_000375.3 | 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 | c.751C>G | p.Leu251Val | missense_variant | 10/10 | 1 | NM_000375.3 | P1 |
Frequencies
GnomAD3 genomes AF: 0.000532 AC: 81AN: 152248Hom.: 0 Cov.: 33
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GnomAD3 exomes AF: 0.000145 AC: 34AN: 234968Hom.: 0 AF XY: 0.0000861 AC XY: 11AN XY: 127752
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GnomAD4 exome AF: 0.0000440 AC: 64AN: 1455446Hom.: 0 Cov.: 30 AF XY: 0.0000304 AC XY: 22AN XY: 723514
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GnomAD4 genome AF: 0.000532 AC: 81AN: 152366Hom.: 0 Cov.: 33 AF XY: 0.000617 AC XY: 46AN XY: 74518
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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:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Benign
T
BayesDel_noAF
Pathogenic
CADD
Uncertain
DANN
Uncertain
DEOGEN2
Uncertain
D;D;D;.;.
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Uncertain
D
LIST_S2
Uncertain
.;.;D;D;T
M_CAP
Uncertain
D
MetaRNN
Benign
T;T;T;T;T
MetaSVM
Pathogenic
D
MutationAssessor
Benign
L;L;L;.;.
MutationTaster
Benign
D;D
PrimateAI
Benign
T
PROVEAN
Benign
N;.;N;.;.
REVEL
Pathogenic
Sift
Pathogenic
D;.;D;.;.
Sift4G
Uncertain
D;.;D;.;.
Polyphen
D;D;D;.;.
Vest4
MVP
MPC
ClinPred
T
GERP RS
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gMVP
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at