rs72557946
Variant summary
Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2
The NM_001395413.1(POR):c.1405G>A(p.Val469Met) variant causes a missense change. The variant allele was found at a frequency of 0.000311 in 1,562,528 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V469L) has been classified as Uncertain significance.
Frequency
Consequence
NM_001395413.1 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Benign. Variant got -13 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
POR | NM_001395413.1 | c.1405G>A | p.Val469Met | missense_variant | 13/16 | ENST00000461988.6 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
POR | ENST00000461988.6 | c.1405G>A | p.Val469Met | missense_variant | 13/16 | 1 | NM_001395413.1 | P4 |
Frequencies
GnomAD3 genomes AF: 0.00158 AC: 240AN: 152246Hom.: 2 Cov.: 36
GnomAD3 exomes AF: 0.000382 AC: 77AN: 201346Hom.: 1 AF XY: 0.000212 AC XY: 23AN XY: 108730
GnomAD4 exome AF: 0.000174 AC: 246AN: 1410164Hom.: 1 Cov.: 65 AF XY: 0.000158 AC XY: 110AN XY: 694060
GnomAD4 genome AF: 0.00158 AC: 240AN: 152364Hom.: 2 Cov.: 36 AF XY: 0.00158 AC XY: 118AN XY: 74502
ClinVar
Submissions by phenotype
not specified Uncertain:1Benign:1
Uncertain significance, criteria provided, single submitter | clinical testing | Genetic Services Laboratory, University of Chicago | Aug 24, 2018 | - - |
Likely benign, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Jun 02, 2023 | Variant summary: POR c.1405G>A (p.Val469Met) results in a conservative amino acid change in the encoded protein sequence. Two of three in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00038 in 203030 control chromosomes, predominantly at a frequency of 0.0053 within the African or African-American subpopulation in the gnomAD database, including 1 homozygote. The observed variant frequency within African or African-American control individuals in the gnomAD database is approximately 6 fold of the estimated maximal expected allele frequency for a pathogenic variant in POR causing Congenital Adrenal Hyperplasia phenotype (0.00091), strongly suggesting that the variant is a benign polymorphism found primarily in populations of African or African-American origin. To our knowledge, no occurrence of c.1405G>A in individuals affected with Congenital Adrenal Hyperplasia has been reported. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in >50%-90% of normal cytochrome P450 enzyme activity (Agrawal_2008). The following publications have been ascertained in the context of this evaluation (PMID: 18551037, 18230729). Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation, classifying the variant as likely benign (n=2) or uncertain significance (n=2). Based on the evidence outlined above, the variant was classified as likely benign. - |
not provided Uncertain:1Benign:1
Likely benign, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Jul 02, 2020 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Mar 30, 2023 | Has not been previously published as pathogenic or benign to our knowledge; Published functional studies demonstrate a significant reduction in catalytic activity compared to wildtype (Huang et al., 2008); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 18551037, 18230729) - |
POR-related disorder Benign:1
Likely benign, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Jul 08, 2019 | 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). - |
Congenital adrenal hyperplasia due to cytochrome P450 oxidoreductase deficiency Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Invitae | Oct 05, 2022 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at