chr7-75981558-C-T

Position:

chr7-75981558-C-T

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_001395413.1(POR):c.674C>T(p.Pro225Leu) variant causes a missense change. The variant allele was found at a frequency of 0.0035 in 1,613,044 control chromosomes in the GnomAD database, including 13 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. P225P) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0026 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0036 ( 13 hom. )

Consequence

POR
NM_001395413.1 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4B:4

Conservation

PhyloP100: 5.86

Variant links:

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]

POR links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.038654447).

BP6

Variant 7-75981558-C-T is Benign according to our data. Variant chr7-75981558-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 436385.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=3, Uncertain_significance=4}.

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00257 (392/152314) while in subpopulation NFE AF= 0.00425 (289/68018). AF 95% confidence interval is 0.00385. There are 0 homozygotes in gnomad4. There are 168 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

BS2

High Homozygotes in GnomAdExome4 at 13 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
POR	NM_001395413.1 linkuse as main transcript	c.674C>T	p.Pro225Leu	missense_variant	7/16	ENST00000461988.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
POR	ENST00000461988.6 linkuse as main transcript	c.674C>T	p.Pro225Leu	missense_variant	7/16	1	NM_001395413.1	P4

Frequencies

GnomAD3 genomes

AF:

0.00258

AC:

392

AN:

152196

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000796

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00242

Gnomad ASJ

AF:

0.00288

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.000414

Gnomad FIN

AF:

0.00151

Gnomad MID

AF:

0.00633

Gnomad NFE

AF:

0.00425

Gnomad OTH

AF:

0.000955

GnomAD3 exomes

AF:

0.00248

AC:

610

AN:

245926

Hom.:

AF XY:

0.00243

AC XY:

326

AN XY:

134052

show subpopulations

Gnomad AFR exome

AF:

0.000929

Gnomad AMR exome

AF:

0.000758

Gnomad ASJ exome

AF:

0.00131

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000197

Gnomad FIN exome

AF:

0.00209

Gnomad NFE exome

AF:

0.00443

Gnomad OTH exome

AF:

0.00235

GnomAD4 exome

AF:

0.00360

AC:

5258

AN:

1460730

Hom.:

Cov.:

AF XY:

0.00356

AC XY:

2587

AN XY:

726612

show subpopulations

Gnomad4 AFR exome

AF:

0.000598

Gnomad4 AMR exome

AF:

0.000851

Gnomad4 ASJ exome

AF:

0.00184

Gnomad4 EAS exome

AF:

0.0000504

Gnomad4 SAS exome

AF:

0.000267

Gnomad4 FIN exome

AF:

0.00229

Gnomad4 NFE exome

AF:

0.00437

Gnomad4 OTH exome

AF:

0.00230

GnomAD4 genome

AF:

0.00257

AC:

392

AN:

152314

Hom.:

Cov.:

AF XY:

0.00226

AC XY:

168

AN XY:

74486

show subpopulations

Gnomad4 AFR

AF:

0.000794

Gnomad4 AMR

AF:

0.00242

Gnomad4 ASJ

AF:

0.00288

Gnomad4 EAS

AF:

0.000194

Gnomad4 SAS

AF:

0.000414

Gnomad4 FIN

AF:

0.00151

Gnomad4 NFE

AF:

0.00425

Gnomad4 OTH

AF:

0.000945

Alfa

AF:

0.00331

Hom.:

Bravo

AF:

0.00247

TwinsUK

AF:

0.00405

AC:

ALSPAC

AF:

0.00519

AC:

ESP6500AA

AF:

0.000738

AC:

ESP6500EA

AF:

0.00478

AC:

ExAC

AF:

0.00265

AC:

320

EpiCase

AF:

0.00365

EpiControl

AF:

0.00380

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:4Benign:4

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:2Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Oct 26, 2023	The POR c.683C>T; p.Pro228Leu variant (rs17853284), which is part of the POR*36 allele (Gomes 2009), has been reported to have 40 to 100 percent P450 oxidoreductase activity in assays on CYP2C19, CYP17A1, NADPH Ox, Cyt c Red, CYP17A1, CYP3A4 and HO-1 enzymes (Agrawl 2008, Huang 2005, Marohnic 2001, Moutinho 2012, Pandey 2010), and 20 percent activity on CYP1A2 (Agrawal 2008). The p.Pro228Leu variant is listed in ClinVar (Variation ID: 436385), and is found in the general population with an overall allele frequency of 0.25% (689/277308 alleles, including a single homozygote) in the Genome Aggregation Database. The proline at position 228 is highly conserved, and computational analyses (SIFT, PolyPhen-2) predict that this variant is deleterious. Although the functional assays suggest that the p.Pro228Leu may be a benign polymorphism, there is insufficient information to determine its clinical significance with certainty. References: Agrawal V et al. Pharmacogenetics of P450 oxidoreductase: effect of sequence variants on activities of CYP1A2 and CYP2C19. Pharmacogenet Genomics. 2008; 18(7):569-76. Gomes A et al. Pharmacogenomics of human liver cytochrome P450 oxidoreductase: multifactorial analysis and impact on microsomal drug oxidation. Pharmacogenomics. 2009; 10(4):579-99. Huang N et al. Diversity and function of mutations in p450 oxidoreductase in patients with Antley-Bixler syndrome and disordered steroidogenesis. Am J Hum Genet. 2005; 76(5):729-49. Marohnic C et al. Mutations of human cytochrome P450 reductase differentially modulate heme oxygenase-1 activity and oligomerization. Arch Biochem Biophys. 2011;513(1):42-50. Moutinho D et al. Altered human CYP3A4 activity caused by Antley-Bixler syndrome-related variants of NADPH-cytochrome P450 oxidoreductase measured in a robust in vitro system. Drug Metab Dispos. 2012; 40(4):754-60. Pandey A et al. Altered heme catabolism by heme oxygenase-1 caused by mutations in human NADPH cytochrome P450 reductase. Biochem Biophys Res Commun. 2010; 400(3):374-8. -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 02, 2021	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 26582918, 16467261, 27032764, 27068427, 27496950, 21084761, 22462747, 20732302, 21741353, 18551037, 20981092, 17635179, 22252407, 30496128) -
Uncertain significance, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Sep 27, 2022	- -

not specified

Uncertain:1Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Sep 20, 2016	- -
Likely benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Nov 28, 2017	- -

Congenital adrenal hyperplasia due to cytochrome P450 oxidoreductase deficiency

Uncertain:1Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 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). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -
Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -

POR-related disorder

Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Apr 11, 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). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Uncertain

0.088

BayesDel_noAF

Pathogenic

0.35

CADD

Pathogenic

DANN

Uncertain

1.0

Eigen

Uncertain

0.47

Eigen_PC

Uncertain

0.41

FATHMM_MKL

Uncertain

0.95

M_CAP

Pathogenic

0.32

MetaRNN

Benign

0.039

T;T

MetaSVM

Uncertain

0.36

MutationTaster

Benign

1.0

D;D;D;D;D

PrimateAI

Uncertain

0.78

PROVEAN

Pathogenic

-8.6

D;D

REVEL

Uncertain

0.55

Sift

Uncertain

0.0010

D;D

Sift4G

Uncertain

0.049

D;T

Vest4

0.88

MVP

0.88

MPC

0.40

ClinPred

0.070

GERP RS

3.7

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

gMVP

0.62

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over