rs121912974

Positions:

chr7-75983548-G-C

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM1PM2PP3_ModeratePP5_Very_Strong

The ENST00000461988.6(POR):c.850G>C(p.Ala284Pro) variant causes a missense change. The variant allele was found at a frequency of 0.000312 in 1,612,888 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★).

Frequency

Genomes: 𝑓 0.00021 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00032 ( 0 hom. )

Consequence

POR
ENST00000461988.6 missense

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:9U:1O:1

Conservation

PhyloP100: 6.34

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 Pathogenic. Variant got 14 ACMG points.

PM1

In a domain FAD-binding FR-type (size 242) in uniprot entity NCPR_HUMAN there are 12 pathogenic changes around while only 5 benign (71%) in ENST00000461988.6

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.858

PP5

Variant 7-75983548-G-C is Pathogenic according to our data. Variant chr7-75983548-G-C is described in ClinVar as [Pathogenic]. Clinvar id is 16902.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-75983548-G-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
POR	NM_001395413.1 linkuse as main transcript	c.850G>C	p.Ala284Pro	missense_variant	9/16	ENST00000461988.6	NP_001382342.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
POR	ENST00000461988.6 linkuse as main transcript	c.850G>C	p.Ala284Pro	missense_variant	9/16	1	NM_001395413.1	ENSP00000419970	P4

Frequencies

GnomAD3 genomes

AF:

0.000210

AC:

AN:

152026

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000483

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000378

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000382

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000241

AC:

AN:

249026

Hom.:

AF XY:

0.000252

AC XY:

AN XY:

135154

show subpopulations

Gnomad AFR exome

AF:

0.0000646

Gnomad AMR exome

AF:

0.0000290

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000603

Gnomad NFE exome

AF:

0.000372

Gnomad OTH exome

AF:

0.000496

GnomAD4 exome

AF:

0.000322

AC:

471

AN:

1460862

Hom.:

Cov.:

AF XY:

0.000312

AC XY:

227

AN XY:

726700

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.0000224

Gnomad4 ASJ exome

AF:

0.0000383

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.000380

Gnomad4 NFE exome

AF:

0.000384

Gnomad4 OTH exome

AF:

0.000348

GnomAD4 genome

AF:

0.000210

AC:

AN:

152026

Hom.:

Cov.:

AF XY:

0.000148

AC XY:

AN XY:

74248

show subpopulations

Gnomad4 AFR

AF:

0.0000483

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.000378

Gnomad4 NFE

AF:

0.000382

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000447

Hom.:

Bravo

AF:

0.000268

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000475

AC:

ExAC

AF:

0.000223

AC:

EpiCase

AF:

0.000164

EpiControl

AF:

0.000237

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:9Uncertain:1Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Congenital adrenal hyperplasia due to cytochrome P450 oxidoreductase deficiency

Pathogenic:3Other:1

not provided, no classification provided	literature only	GeneReviews	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	Feb 02, 2022	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with Antley-Bixler syndrome with genital anomalies and disordered steroidogenesis (MIM#201750), and disordered steroidogenesis due to cytochrome P450 oxidoreductase (MIM#613571). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0200 - Variant is predicted to result in a missense amino acid change from alanine to proline. (I) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD (v2) <0.01 for a recessive condition (66 heterozygotes, 0 homozygotes). (SP) 0502 - Missense variant with conflicting in silico predictions and uninformative conservation. (I) 0600 - Variant is located in the annotated FAD-binding FR-type domain (Uniprot). (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been reported as pathogenic, and has been observed in many homozygous and compound heterozygous patients with P450 oxidoreductase deficiency. It is regarded as the most common variant in Caucasian populations, and results in a mild-moderate form of disease (ClinVar, PMID: 27068427, PMID: 22162478). (SP) 1002 - This variant has moderate functional evidence supporting abnormal protein function. Functional assays have demonstrated that this variant causes significant reductions in enzyme activity and steroid biosynthesis (PMID: 27068427). (SP) 1205 - This variant has been shown to be maternally inherited. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 07, 2024	This sequence change replaces alanine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 287 of the POR protein (p.Ala287Pro). This variant is present in population databases (rs121912974, gnomAD 0.05%). This missense change has been observed in individuals with POR deficiency (PMID: 14758361, 22162478). ClinVar contains an entry for this variant (Variation ID: 16902). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt POR protein function with a positive predictive value of 80%. Experimental studies have shown that this missense change affects POR function (PMID: 14758361, 18551037, 20940534, 21741353). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, no assertion criteria provided	literature only	OMIM	May 01, 2005	- -

Antley-Bixler syndrome with genital anomalies and disordered steroidogenesis

Pathogenic:2Uncertain:1

Pathogenic, criteria provided, single submitter	clinical testing	Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein	Jan 12, 2023	ACMG classification criteria: PS3 supporting, PM3 very strong, PP3 supporting -
Pathogenic, no assertion criteria provided	literature only	OMIM	May 01, 2005	- -
Uncertain significance, no assertion criteria provided	research	Lupski Lab, Baylor-Hopkins CMG, Baylor College of Medicine	-	- -

POR-related disorder

Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Daryl Scott Lab, Baylor College of Medicine	Feb 01, 2022	- -
Pathogenic, no assertion criteria provided	clinical testing	PreventionGenetics, part of Exact Sciences	Aug 12, 2024	The POR c.859G>C variant is predicted to result in the amino acid substitution p.Ala287Pro. This variant has been reported to be the most common pathogenic POR variant found in patients of European ancestry with P450 oxidoreductase deficiency (see for example, Fluck et al. 2004. PubMed ID: 14758361; Krone et al. 2012. PubMed ID: 22162478). This variant is reported in 0.05% of alleles in individuals of European (Finnish) descent in gnomAD. This variant is interpreted as pathogenic. -

not provided

Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Nov 21, 2022	Published functional studies demonstrate a decreased rate of flavin reduction and conformational protein instability leading to proteolytic susceptibility (Jin et al., 2015; McCammon et al., 2016); 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: 21741353, 20732302, 22252407, 19621255, 15793702, 17389698, 19837910, 17505056, 17635179, 16495354, 17062779, 25728647, 18551037, 20697309, 20940534, 22547083, 22719896, 14758361, 26969897, 26670660, 27496950, 18259105, 12116245, 15220035, 31230720, 31837199, 31980526, 32242900, 34426522, 31589614, 31128914, 35842891, 22162478, 21190981) -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Oct 04, 2020	- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.21

BayesDel_noAF

Pathogenic

0.40

CADD

Pathogenic

DANN

Uncertain

1.0

Eigen

Uncertain

0.63

Eigen_PC

Uncertain

0.61

FATHMM_MKL

Uncertain

0.91

LIST_S2

Pathogenic

0.99

.;.;D

M_CAP

Uncertain

0.22

MetaRNN

Pathogenic

0.86

D;D;D

MetaSVM

Uncertain

0.73

MutationTaster

Benign

1.0

A;A;A;A;A;A

PrimateAI

Uncertain

0.70

PROVEAN

Uncertain

-3.6

D;D;D

REVEL

Pathogenic

0.89

Sift

Uncertain

0.0030

D;D;D

Sift4G

Uncertain

0.011

D;D;D

Vest4

0.75

MVP

0.94

MPC

0.59

ClinPred

0.83

GERP RS

5.2

gMVP

0.96

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.080

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