rs1057868

Positions:

chr7-75985688-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_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. 12/17 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar 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

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 -20 ACMG points.

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 [Likely_benign]. Clinvar id is 256840.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-75985688-C-T is described in Lovd as [Pathogenic]. Variant chr7-75985688-C-T is described in Lovd as [Benign].

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/exons	MANE	Protein	UniProt
POR	NM_001395413.1 linkuse as main transcript	c.1499C>T	p.Ala500Val	missense_variant	13/16	ENST00000461988.6	NP_001382342.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
POR	ENST00000461988.6 linkuse as main transcript	c.1499C>T	p.Ala500Val	missense_variant	13/16	1	NM_001395413.1	ENSP00000419970	P4

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

GnomAD3 exomes

AF:

0.305

AC:

64499

AN:

211366

Hom.:

9927

AF XY:

0.309

AC XY:

35621

AN XY:

115164

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 SAS exome

AF:

0.354

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

Gnomad4 AFR exome

AF:

0.176

Gnomad4 AMR exome

AF:

0.284

Gnomad4 ASJ exome

AF:

0.262

Gnomad4 EAS exome

AF:

0.401

Gnomad4 SAS exome

AF:

0.353

Gnomad4 FIN exome

AF:

0.405

Gnomad4 NFE exome

AF:

0.285

Gnomad4 OTH exome

AF:

0.285

GnomAD4 genome

AF:

0.273

AC:

41507

AN:

152272

Hom.:

6048

Cov.:

AF XY:

0.282

AC XY:

21029

AN XY:

74454

show subpopulations

Gnomad4 AFR

AF:

0.184

Gnomad4 AMR

AF:

0.293

Gnomad4 ASJ

AF:

0.257

Gnomad4 EAS

AF:

0.382

Gnomad4 SAS

AF:

0.357

Gnomad4 FIN

AF:

0.414

Gnomad4 NFE

AF:

0.286

Gnomad4 OTH

AF:

0.276

Alfa

AF:

0.286

Hom.:

5563

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

Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	This variant is associated with the following publications: (PMID: 26227094, 26123203, 16467261, 18230729, 24113216, 19801957, 22547083, 20940534, 20697309, 18551037, 17635179, 20732302) -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 29, 2023	- -

not specified

Benign:2

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Dec 03, 2021	- -

Congenital adrenal hyperplasia due to cytochrome P450 oxidoreductase deficiency

Benign:2

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Mar 06, 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	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -

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_addAF

Benign

-0.49

BayesDel_noAF

Benign

-0.33

CADD

Benign

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

MutationTaster

Benign

1.0

P;P;P;P;P;P

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

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

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