rs72557946

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. The variant received -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

Genomes: 𝑓 0.0016 ( 2 hom., cov: 36)

Exomes 𝑓: 0.00017 ( 1 hom. )

Consequence

POR
NM_001395413.1 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:4

Conservation

PhyloP100: 5.04

Publications

7 publications found

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 Gene-Disease associations (from GenCC):

Antley-Bixler syndrome with genital anomalies and disordered steroidogenesis
Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: ClinGen, PanelApp Australia, Ambry Genetics
congenital adrenal hyperplasia due to cytochrome P450 oxidoreductase deficiency
Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet
Antley-Bixler syndrome
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

POR links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -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 VariationId is 718192.

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 the male GnomAd4 subpopulation. Median coverage is 36. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 2 AR,AD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
POR	NM_001395413.1 link	c.1405G>A	p.Val469Met	missense_variant	Exon 13 of 16	ENST00000461988.6	NP_001382342.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
POR	ENST00000461988.6 link	c.1405G>A	p.Val469Met	missense_variant	Exon 13 of 16	1	NM_001395413.1	ENSP00000419970.2		P16435

Frequencies

GnomAD3 genomes

AF:

0.00158

AC:

240

AN:

152246

Hom.:

Cov.:

show subpopulations

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

GnomAD2 exomes

AF:

0.000382

AC:

AN:

201346

AF XY:

0.000212

show subpopulations

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 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.:

Cov.:

AF XY:

0.000158

AC XY:

110

AN XY:

694060

show subpopulations

African (AFR)

AF:

0.00620

AC:

203

AN:

32758

American (AMR)

AF:

0.000362

AC:

AN:

41446

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

23316

East Asian (EAS)

AF:

0.00

AC:

AN:

38632

South Asian (SAS)

AF:

0.0000128

AC:

AN:

78120

European-Finnish (FIN)

AF:

0.00

AC:

AN:

49388

Middle Eastern (MID)

AF:

0.000362

AC:

AN:

5524

European-Non Finnish (NFE)

AF:

9.24e-7

AC:

AN:

1082748

Other (OTH)

AF:

0.000412

AC:

AN:

58232

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.479

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00158

AC:

240

AN:

152364

Hom.:

Cov.:

AF XY:

0.00158

AC XY:

118

AN XY:

74502

show subpopulations

African (AFR)

AF:

0.00541

AC:

225

AN:

41590

American (AMR)

AF:

0.000588

AC:

AN:

15308

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5174

South Asian (SAS)

AF:

0.00

AC:

AN:

4834

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10628

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

68038

Other (OTH)

AF:

0.00284

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.498

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.000693

Hom.:

Bravo

AF:

0.00177

ESP6500AA

AF:

0.00246

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.000385

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2Benign:4

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not specified

Uncertain:1Benign:1

Aug 24, 2018

Genetic Services Laboratory, University of Chicago

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jun 02, 2023

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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

Mar 30, 2023

GeneDx

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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) -

Jul 02, 2020

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

POR-related disorder

Benign:1

Jul 08, 2019

PreventionGenetics, part of Exact Sciences

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

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

Jan 09, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.34

BayesDel_addAF

Benign

-0.30

BayesDel_noAF

Benign

-0.21

CADD

Uncertain

(source)

DANN

Uncertain

1.0

Eigen

Uncertain

0.57

Eigen_PC

Uncertain

0.42

FATHMM_MKL

Uncertain

0.77

LIST_S2

Uncertain

0.96

.;.;D

M_CAP

Pathogenic

0.39

MetaRNN

Benign

0.022

T;T;T

MetaSVM

Uncertain

0.097

PhyloP100

5.0

PrimateAI

Uncertain

0.79

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

GERP RS

3.3

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

gMVP

0.42

Mutation Taster

=76/24

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over