chr7-75954061-ATC-A
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Variant summary
Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1PM2PP5_Moderate
The NM_001395413.1(POR):c.64_65del(p.Leu22PhefsTer93) variant causes a frameshift change. The variant allele was found at a frequency of 0.00000137 in 1,460,092 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★).
Frequency
Genomes: not found (cov: 32)
Exomes 𝑓: 0.0000014 ( 0 hom. )
Consequence
POR
NM_001395413.1 frameshift
NM_001395413.1 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 4.03
Genes affected
POR (HGNC:9208): (cytochrome p450 oxidoreductase) This gene encodes an endoplasmic reticulum membrane oxidoreductase that is essential for multiple metabolic processes, including reactions catalyzed by cytochrome P450 proteins for metabolism of steroid hormones, drugs and xenobiotics. The encoded protein has a flavin adenine dinucleotide (FAD)-binding domain and a flavodoxin-like domain which bind two cofactors, FAD and FMN, that allow it to donate electrons directly from NADPH to all microsomal P450 enzymes. Mutations in this gene cause a complex set of disorders, including apparent combined P450C17 and P450C21 deficiency, amenorrhea and disordered steroidogenesis, congenital adrenal hyperplasia and Antley-Bixler syndrome, that resemble those caused by defects in steroid metabolizing enzymes such as aromatase, 21-hydroxylase, and 17 alpha-hydroxylase. [provided by RefSeq, Aug 2020]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 12 ACMG points.
PVS1
Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant located near the start codon (<100nt), not predicted to undergo nonsense mediated mRNA decay. There are 23 pathogenic variants in the truncated region.
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 7-75954061-ATC-A is Pathogenic according to our data. Variant chr7-75954061-ATC-A is described in ClinVar as [Pathogenic]. Clinvar id is 1920714.Status of the report is criteria_provided_single_submitter, 1 stars.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
POR | NM_001395413.1 | c.64_65del | p.Leu22PhefsTer93 | frameshift_variant | 2/16 | ENST00000461988.6 | NP_001382342.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
POR | ENST00000461988.6 | c.64_65del | p.Leu22PhefsTer93 | frameshift_variant | 2/16 | 1 | NM_001395413.1 | ENSP00000419970 | P4 |
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD3 genomes
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32
GnomAD3 exomes AF: 0.00000813 AC: 2AN: 246148Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 133542
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GnomAD4 exome AF: 0.00000137 AC: 2AN: 1460092Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 726152
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GnomAD4 genome Cov.: 32
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ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:1
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
Congenital adrenal hyperplasia due to cytochrome P450 oxidoreductase deficiency Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Mar 28, 2023 | For these reasons, this variant has been classified as Pathogenic. This premature translational stop signal has been observed in individual(s) with clinical features of cytochrome P450 oxidoreductase deficiency (PMID: 32060549). This variant is present in population databases (rs782696006, gnomAD 0.006%). This sequence change creates a premature translational stop signal (p.Leu25Phefs*93) in the POR gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in POR are known to be pathogenic (PMID: 14758361, 20732302, 21741353). - |
Computational scores
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Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at