rs1057868

Variant names:

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 2P and 20B. PM1BP4_StrongBP6_Very_StrongBA1

The NM_001395413.1(POR):c.1499C>T(p.Ala500Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.291 in 1,591,240 control chromosomes in the GnomAD database, including 69,459 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. A500A) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.27 ( 6048 hom., cov: 36)

Exomes 𝑓: 0.29 ( 63411 hom. )

Consequence

POR
NM_001395413.1 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8

Conservation

PhyloP100: 1.46

Publications

207 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 -18 ACMG points.

PM1

In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 8 uncertain in NM_001395413.1

BP4

Computational evidence support a benign effect (MetaRNN=0.0018226206).

BP6

Variant 7-75985688-C-T is Benign according to our data. Variant chr7-75985688-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 256840.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.368 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
POR	NM_001395413.1 link	c.1499C>T	p.Ala500Val	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.1499C>T	p.Ala500Val	missense_variant	Exon 13 of 16	1	NM_001395413.1	ENSP00000419970.2		P16435

Frequencies

GnomAD3 genomes

AF:

0.273

AC:

41467

AN:

152154

Hom.:

6037

Cov.:

show subpopulations

Gnomad AFR

AF:

0.183

Gnomad AMI

AF:

0.344

Gnomad AMR

AF:

0.293

Gnomad ASJ

AF:

0.257

Gnomad EAS

AF:

0.382

Gnomad SAS

AF:

0.358

Gnomad FIN

AF:

0.414

Gnomad MID

AF:

0.215

Gnomad NFE

AF:

0.286

Gnomad OTH

AF:

0.275

GnomAD2 exomes

AF:

0.305

AC:

64499

AN:

211366

AF XY:

0.309

show subpopulations

Gnomad AFR exome

AF:

0.184

Gnomad AMR exome

AF:

0.282

Gnomad ASJ exome

AF:

0.261

Gnomad EAS exome

AF:

0.374

Gnomad FIN exome

AF:

0.409

Gnomad NFE exome

AF:

0.287

Gnomad OTH exome

AF:

0.304

GnomAD4 exome

AF:

0.293

AC:

421897

AN:

1438968

Hom.:

63411

Cov.:

AF XY:

0.296

AC XY:

210981

AN XY:

713612

show subpopulations

African (AFR)

AF:

0.176

AC:

5843

AN:

33130

American (AMR)

AF:

0.284

AC:

11822

AN:

41590

Ashkenazi Jewish (ASJ)

AF:

0.262

AC:

6701

AN:

25598

East Asian (EAS)

AF:

0.401

AC:

15493

AN:

38654

South Asian (SAS)

AF:

0.353

AC:

29164

AN:

82638

European-Finnish (FIN)

AF:

0.405

AC:

20269

AN:

50002

Middle Eastern (MID)

AF:

0.291

AC:

1669

AN:

5726

European-Non Finnish (NFE)

AF:

0.285

AC:

313960

AN:

1102086

Other (OTH)

AF:

0.285

AC:

16976

AN:

59544

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.479

Heterozygous variant carriers

19686

39372

59057

78743

98429

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

10554

21108

31662

42216

52770

<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:

0.273

AC:

41507

AN:

152272

Hom.:

6048

Cov.:

AF XY:

0.282

AC XY:

21029

AN XY:

74454

show subpopulations

African (AFR)

AF:

0.184

AC:

7635

AN:

41562

American (AMR)

AF:

0.293

AC:

4487

AN:

15304

Ashkenazi Jewish (ASJ)

AF:

0.257

AC:

892

AN:

3470

East Asian (EAS)

AF:

0.382

AC:

1975

AN:

5172

South Asian (SAS)

AF:

0.357

AC:

1723

AN:

4830

European-Finnish (FIN)

AF:

0.414

AC:

4389

AN:

10606

Middle Eastern (MID)

AF:

0.224

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.286

AC:

19443

AN:

68010

Other (OTH)

AF:

0.276

AC:

583

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.498

Heterozygous variant carriers

1646

3293

4939

6586

8232

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

440

880

1320

1760

2200

<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:

0.285

Hom.:

15285

Bravo

AF:

0.256

TwinsUK

AF:

0.281

AC:

1043

ALSPAC

AF:

0.279

AC:

1077

ESP6500AA

AF:

0.168

AC:

698

ESP6500EA

AF:

0.271

AC:

2247

ExAC

AF:

0.276

AC:

32305

Asia WGS

AF:

0.336

AC:

1170

AN:

3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Mar 03, 2015

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is associated with the following publications: (PMID: 26227094, 26123203, 16467261, 18230729, 24113216, 19801957, 22547083, 20940534, 20697309, 18551037, 17635179, 20732302) -

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Nov 25, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not specified

Benign:2

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Dec 03, 2021

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

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Congenital adrenal hyperplasia due to cytochrome P450 oxidoreductase deficiency

Benign:2

Mar 06, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency

Benign:1

Pecori Giraldi Lab, University of Milan

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:case-control

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.069

BayesDel_addAF

Benign

-0.49

BayesDel_noAF

Benign

-0.33

CADD

Benign

(source)

DANN

Uncertain

0.98

Eigen

Benign

-0.86

Eigen_PC

Benign

-0.83

FATHMM_MKL

Benign

0.11

LIST_S2

Benign

0.67

.;.;T

MetaRNN

Benign

0.0018

T;T;T

MetaSVM

Benign

-1.0

PhyloP100

1.5

PrimateAI

Benign

0.37

PROVEAN

Benign

-0.67

N;N;N

REVEL

Benign

0.13

Sift

Benign

0.22

T;T;T

Sift4G

Benign

0.29

T;T;T

Vest4

0.077

MPC

0.11

ClinPred

0.0031

GERP RS

3.5

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

gMVP

0.26

Mutation Taster

=95/5

polymorphism (auto)

(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