10-125788926-G-A
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Variant summary
Our verdict is Benign. Variant got -12 ACMG points: 4P and 16B. PM1PM2BP4_StrongBP6_Very_StrongBS1
The NM_000375.3(UROS):c.740C>T(p.Thr247Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000156 in 1,609,414 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 0.00028 ( 0 hom., cov: 33)
Exomes 𝑓: 0.00014 ( 0 hom. )
Consequence
UROS
NM_000375.3 missense
NM_000375.3 missense
Scores
5
8
5
Clinical Significance
Conservation
PhyloP100: 3.08
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 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=0.016776979).
BP6
Variant 10-125788926-G-A is Benign according to our data. Variant chr10-125788926-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 878599.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
BS1
Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.000282 (43/152374) while in subpopulation EAS AF= 0.00578 (30/5186). AF 95% confidence interval is 0.00416. There are 0 homozygotes in gnomad4. There are 20 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.740C>T | p.Thr247Met | missense_variant | 10/10 | ENST00000368797.10 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
UROS | ENST00000368797.10 | c.740C>T | p.Thr247Met | missense_variant | 10/10 | 1 | NM_000375.3 | P1 |
Frequencies
GnomAD3 genomes AF: 0.000282 AC: 43AN: 152256Hom.: 0 Cov.: 33
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GnomAD3 exomes AF: 0.000353 AC: 84AN: 238238Hom.: 0 AF XY: 0.000285 AC XY: 37AN XY: 129600
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GnomAD4 exome AF: 0.000143 AC: 208AN: 1457040Hom.: 0 Cov.: 30 AF XY: 0.000133 AC XY: 96AN XY: 724482
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GnomAD4 genome AF: 0.000282 AC: 43AN: 152374Hom.: 0 Cov.: 33 AF XY: 0.000268 AC XY: 20AN XY: 74514
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ClinVar
Significance: Likely benign
Submissions summary: Benign:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Cutaneous porphyria Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Apr 28, 2017 | This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. - |
not provided Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Invitae | Jun 06, 2021 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Benign
T
BayesDel_noAF
Uncertain
CADD
Pathogenic
DANN
Uncertain
DEOGEN2
Pathogenic
D;D;D;.;.
Eigen
Pathogenic
Eigen_PC
Uncertain
FATHMM_MKL
Uncertain
D
M_CAP
Uncertain
D
MetaRNN
Benign
T;T;T;T;T
MetaSVM
Pathogenic
D
MutationAssessor
Pathogenic
M;M;M;.;.
MutationTaster
Benign
D;D
PrimateAI
Benign
T
PROVEAN
Uncertain
D;.;D;.;.
REVEL
Pathogenic
Sift
Uncertain
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