chr7-75985969-G-A

Variant names:

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_001395413.1(POR):c.1707G>A(p.Ser569Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.332 in 1,584,318 control chromosomes in the GnomAD database, including 92,226 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.28 ( 6752 hom., cov: 35)

Exomes 𝑓: 0.34 ( 85474 hom. )

Consequence

POR
NM_001395413.1 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:10

Conservation

PhyloP100: -2.87

Publications

28 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 -21 ACMG points.

BP4

Computational evidence support a benign effect (REVEL=0.008).

BP6

Variant 7-75985969-G-A is Benign according to our data. Variant chr7-75985969-G-A is described in ClinVar as Benign. ClinVar VariationId is 256841.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-2.87 with no splicing effect.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.363 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
POR	NM_001395413.1 link	c.1707G>A	p.Ser569Ser	synonymous_variant	Exon 14 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.1707G>A	p.Ser569Ser	synonymous_variant	Exon 14 of 16	1	NM_001395413.1	ENSP00000419970.2		P16435

Frequencies

GnomAD3 genomes

AF:

0.281

AC:

42811

AN:

152156

Hom.:

6756

Cov.:

show subpopulations

Gnomad AFR

AF:

0.167

Gnomad AMI

AF:

0.339

Gnomad AMR

AF:

0.263

Gnomad ASJ

AF:

0.279

Gnomad EAS

AF:

0.0341

Gnomad SAS

AF:

0.274

Gnomad FIN

AF:

0.325

Gnomad MID

AF:

0.266

Gnomad NFE

AF:

0.367

Gnomad OTH

AF:

0.297

GnomAD2 exomes

AF:

0.280

AC:

55733

AN:

199364

AF XY:

0.287

show subpopulations

Gnomad AFR exome

AF:

0.153

Gnomad AMR exome

AF:

0.187

Gnomad ASJ exome

AF:

0.285

Gnomad EAS exome

AF:

0.0264

Gnomad FIN exome

AF:

0.327

Gnomad NFE exome

AF:

0.360

Gnomad OTH exome

AF:

0.288

GnomAD4 exome

AF:

0.338

AC:

483426

AN:

1432044

Hom.:

85474

Cov.:

AF XY:

0.336

AC XY:

238466

AN XY:

709674

show subpopulations

African (AFR)

AF:

0.158

AC:

5201

AN:

33018

American (AMR)

AF:

0.196

AC:

7888

AN:

40176

Ashkenazi Jewish (ASJ)

AF:

0.281

AC:

7191

AN:

25624

East Asian (EAS)

AF:

0.0356

AC:

1364

AN:

38270

South Asian (SAS)

AF:

0.275

AC:

22582

AN:

82196

European-Finnish (FIN)

AF:

0.332

AC:

16389

AN:

49426

Middle Eastern (MID)

AF:

0.278

AC:

1581

AN:

5690

European-Non Finnish (NFE)

AF:

0.367

AC:

402719

AN:

1098376

Other (OTH)

AF:

0.312

AC:

18511

AN:

59268

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.491

Heterozygous variant carriers

21127

42255

63382

84510

105637

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

12528

25056

37584

50112

62640

<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:

0.281

AC:

42811

AN:

152274

Hom.:

6752

Cov.:

AF XY:

0.277

AC XY:

20593

AN XY:

74462

show subpopulations

African (AFR)

AF:

0.167

AC:

6961

AN:

41566

American (AMR)

AF:

0.263

AC:

4021

AN:

15304

Ashkenazi Jewish (ASJ)

AF:

0.279

AC:

967

AN:

3472

East Asian (EAS)

AF:

0.0338

AC:

175

AN:

5184

South Asian (SAS)

AF:

0.274

AC:

1324

AN:

4826

European-Finnish (FIN)

AF:

0.325

AC:

3447

AN:

10620

Middle Eastern (MID)

AF:

0.245

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.367

AC:

24919

AN:

67988

Other (OTH)

AF:

0.292

AC:

616

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

1680

3360

5039

6719

8399

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

420

840

1260

1680

2100

<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:

0.329

Hom.:

27441

Bravo

AF:

0.267

Asia WGS

AF:

0.156

AC:

543

AN:

3476

ClinVar

Significance: Benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:3

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Congenital adrenal hyperplasia due to cytochrome P450 oxidoreductase deficiency

Benign:3

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jan 13, 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. -

Jun 24, 2022

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Benign. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with disordered steroidogenesis due to cytochrome P450 oxidoreductase (MIM#613571) and Antley-Bixler syndrome with genital anomalies and disordered steroidogenesis (MIM#201750). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0212 - Non-canonical splice site variant without proven consequence on splicing (no functional evidence available). (I) 0252 - This variant is homozygous. (I) 0308 - Population frequency for this variant is out of keeping with known incidence of disordered steroidogenesis due to cytochrome P450 oxidoreductase (MIM#613571) and Antley-Bixler syndrome with genital anomalies and disordered steroidogenesis (MIM#201750) (gnomAD v2: 44162 heterozygotes, 10290 homozygotes). (SB) 0506 - Abnormal splicing is not predicted and nucleotide is poorly conserved. (SB) 0600 - Variant is located in the annotated oxidoreductase NAD-binding domain (DECIPHER). (I) 0705 - No comparable single nucleotide substitution variants have previous evidence for pathogenicity. (I) 0805 - This variant has strong previous evidence of being benign in unrelated individuals. It has frequently been reported as benign or a polymorphism, including in individuals with POH or 21 hydroxylase deficiency (ClinVar, PMIDs: 27376429, 33666875). (SB) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -

not provided

Benign:3

Nov 29, 2023

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Mar 03, 2015

GeneDx

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

BayesDel_noAF

Benign

-0.85

CADD

Benign

0.0090

(source)

DANN

Benign

0.93

PhyloP100

-2.9

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Mutation Taster

=100/0

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.11

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