rs28931608

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PM5PP3_ModeratePP5_Very_Strong

The NM_001395413.1(POR):c.1361G>A(p.Arg454His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000407 in 1,597,524 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 13/20 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R454L) has been classified as Likely pathogenic.

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000043 ( 0 hom. )

Consequence

POR
NM_001395413.1 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:9O:1

Conservation

PhyloP100: 7.93

Publications

81 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 Submitted by: ClinGen, 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: Pathogenic. The variant received 12 ACMG points.

PM5

Other missense variant is known to change same aminoacid residue: Variant chr7-75985179-G-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 3251474.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.861

PP5

Variant 7-75985179-G-A is Pathogenic according to our data. Variant chr7-75985179-G-A is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 16907.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001395413.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
POR	NM_001395413.1	MANE Select	c.1361G>A	p.Arg454His	missense	Exon 12 of 16	NP_001382342.1	P16435
POR	NM_001382655.3		c.1415G>A	p.Arg472His	missense	Exon 13 of 17	NP_001369584.2
POR	NM_001367562.3		c.1361G>A	p.Arg454His	missense	Exon 13 of 17	NP_001354491.2	P16435

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
POR	ENST00000461988.6	TSL:1 MANE Select	c.1361G>A	p.Arg454His	missense	Exon 12 of 16	ENSP00000419970.2	P16435
POR	ENST00000447222.5	TSL:5	c.1520G>A	p.Arg507His	missense	Exon 11 of 15	ENSP00000393527.1	H0Y4R2
POR	ENST00000910548.1		c.1361G>A	p.Arg454His	missense	Exon 12 of 16	ENSP00000580607.1

Frequencies

GnomAD3 genomes

AF:

0.0000197

AC:

AN:

152166

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000579

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000517

AC:

AN:

232190

AF XY:

0.0000623

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000563

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000930

Gnomad OTH exome

AF:

0.000172

GnomAD4 exome

AF:

0.0000429

AC:

AN:

1445240

Hom.:

Cov.:

AF XY:

0.0000389

AC XY:

AN XY:

719242

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33454

American (AMR)

AF:

0.00

AC:

AN:

44540

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26024

East Asian (EAS)

AF:

0.00129

AC:

AN:

39642

South Asian (SAS)

AF:

0.00

AC:

AN:

86068

European-Finnish (FIN)

AF:

0.00

AC:

AN:

39268

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5762

European-Non Finnish (NFE)

AF:

0.00000811

AC:

AN:

1110354

Other (OTH)

AF:

0.0000333

AC:

AN:

60128

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.488

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

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:

0.0000197

AC:

AN:

152284

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74464

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41566

American (AMR)

AF:

0.00

AC:

AN:

15296

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.000580

AC:

AN:

5170

South Asian (SAS)

AF:

0.00

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10618

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

68014

Other (OTH)

AF:

0.00

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.558

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.000232

Hom.:

Bravo

AF:

0.0000340

ExAC

AF:

0.0000667

AC:

EpiCase

AF:

0.00

EpiControl

AF:

0.0000594

ClinVar

ClinVar submissions

Significance:Pathogenic/Likely pathogenic

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Congenital adrenal hyperplasia due to cytochrome P450 oxidoreductase deficiency (5)

Antley-Bixler syndrome with genital anomalies and disordered steroidogenesis (2)

not provided (2)

Congenital adrenal hyperplasia due to cytochrome P450 oxidoreductase deficiency;C3150099:Antley-Bixler syndrome with genital anomalies and disordered steroidogenesis (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.99

BayesDel_addAF

Pathogenic

0.33

BayesDel_noAF

Pathogenic

0.57

CADD

Pathogenic

(source)

DANN

Pathogenic

1.0

Eigen

Pathogenic

0.94

Eigen_PC

Pathogenic

0.79

FATHMM_MKL

Uncertain

0.96

LIST_S2

Pathogenic

1.0

M_CAP

Pathogenic

0.54

MetaRNN

Pathogenic

0.86

MetaSVM

Pathogenic

1.1

PhyloP100

7.9

PrimateAI

Pathogenic

0.87

PROVEAN

Pathogenic

-4.9

REVEL

Pathogenic

0.96

Sift

Uncertain

0.0040

Sift4G

Pathogenic

0.0

Vest4

0.98

MVP

0.98

MPC

0.61

ClinPred

0.95

GERP RS

4.3

gMVP

0.83

Mutation Taster

=2/98

disease causing (ClinVar)

(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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over