rs1057870

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_001395413.1(POR):c.1707G>A(p.Ser569=) 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:9

Conservation

PhyloP100: -2.87

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 Benign. Variant got -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.85).

BP6

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

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/exons	MANE	UniProt
POR	NM_001395413.1 linkuse as main transcript	c.1707G>A	p.Ser569=	synonymous_variant	14/16	ENST00000461988.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
POR	ENST00000461988.6 linkuse as main transcript	c.1707G>A	p.Ser569=	synonymous_variant	14/16	1	NM_001395413.1	P4

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

GnomAD3 exomes

AF:

0.280

AC:

55733

AN:

199364

Hom.:

8822

AF XY:

0.287

AC XY:

31161

AN XY:

108600

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 SAS exome

AF:

0.278

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

Gnomad4 AFR exome

AF:

0.158

Gnomad4 AMR exome

AF:

0.196

Gnomad4 ASJ exome

AF:

0.281

Gnomad4 EAS exome

AF:

0.0356

Gnomad4 SAS exome

AF:

0.275

Gnomad4 FIN exome

AF:

0.332

Gnomad4 NFE exome

AF:

0.367

Gnomad4 OTH exome

AF:

0.312

GnomAD4 genome

AF:

0.281

AC:

42811

AN:

152274

Hom.:

6752

Cov.:

AF XY:

0.277

AC XY:

20593

AN XY:

74462

show subpopulations

Gnomad4 AFR

AF:

0.167

Gnomad4 AMR

AF:

0.263

Gnomad4 ASJ

AF:

0.279

Gnomad4 EAS

AF:

0.0338

Gnomad4 SAS

AF:

0.274

Gnomad4 FIN

AF:

0.325

Gnomad4 NFE

AF:

0.367

Gnomad4 OTH

AF:

0.292

Alfa

AF:

0.340

Hom.:

11093

Bravo

AF:

0.267

Asia WGS

AF:

0.156

AC:

543

AN:

3476

ClinVar

Significance: Benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:3

Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

Congenital adrenal hyperplasia due to cytochrome P450 oxidoreductase deficiency

Benign:3

Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	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. -
Benign, criteria provided, single submitter	clinical testing	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	Jun 24, 2022	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:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 29, 2023	- -

Classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency

Benign:1

Benign, criteria provided, single submitter

case-control

Pecori Giraldi Lab, University of Milan

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.85

Cadd

Benign

0.0090

Dann

Benign

0.93

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

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

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