rs72557946

chr7-75985594-G-Achr7-75985594-G-C

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

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:
  • Genomes: 𝑓 0.0016 (2 hom., cov: 36)
  • Exomes 𝑓: 0.00017 (1 hom.)
• Consequence: POR NM_001395413.1 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:4
• Conservation: PhyloP100: 5.04

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]

ACMG classification

Verdict is Benign. Variant got -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.021828085).
• BP6: Variant 7-75985594-G-A is Benign according to our data. Variant chr7-75985594-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 718192.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=4, Uncertain_significance=2}.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00158 (240/152364) while in subpopulation AFR AF= 0.00541 (225/41590). AF 95% confidence interval is 0.00483. There are 2 homozygotes in gnomad4. There are 118 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 2 AR gene

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: 240 AN: 152246 Hom.: 2 Cov.: 36

Gnomad AFR AF: 0.00543

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000589

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: 0.00287

GnomAD3 exomes AF: 0.000382 AC: 77 AN: 201346 Hom.: 1 AF XY: 0.000212 AC XY: 23 AN XY: 108730

Gnomad AFR exome AF: 0.00530

Gnomad AMR exome AF: 0.000290

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: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000174 AC: 246 AN: 1410164 Hom.: 1 Cov.: 65 AF XY: 0.000158 AC XY: 110 AN XY: 694060

Gnomad4 AFR exome AF: 0.00620

Gnomad4 AMR exome AF: 0.000362

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000128

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.24e-7

Gnomad4 OTH exome AF: 0.000412

GnomAD4 genome AF: 0.00158 AC: 240 AN: 152364 Hom.: 2 Cov.: 36 AF XY: 0.00158 AC XY: 118 AN XY: 74502

Gnomad4 AFR AF: 0.00541

Gnomad4 AMR AF: 0.000588

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: 0.00284

Alfa AF: 0.0000346 Hom.: 0

Bravo AF: 0.00177

ESP6500AA AF: 0.00246 AC: 10

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000385 AC: 46

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:4

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not specified Uncertain:1 Benign:1

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. -
Uncertain significance, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Aug 24, 2018	- -

not provided Uncertain:1 Benign: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: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.30	T
BayesDel_noAF	Benign	-0.21
Cadd	Uncertain	24
Dann	Uncertain	1.0
Eigen	Uncertain	0.57
Eigen_PC	Uncertain	0.42
FATHMM_MKL	Uncertain	0.77	D
M_CAP	Pathogenic	0.39	D
MetaRNN	Benign	0.022	T;T;T
MetaSVM	Uncertain	0.097	D
MutationTaster	Benign	1.0	D;D;D;D;D;D
PrimateAI	Uncertain	0.79	T
PROVEAN	Benign	-2.4	N;N;N
REVEL	Uncertain	0.46
Sift	Uncertain	0.0020	D;D;D
Sift4G	Uncertain	0.0030	D;D;D
Vest4		0.51
MVP		0.89
MPC		0.53
ClinPred		0.069	T
GERP RS		3.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
gMVP		0.42

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

Other links and lift over

dbSNP: rs72557946; hg19: chr7-75614912;