rs1135612

Positions:

Variant summary

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

The NM_001395413.1(POR):c.378A>G(p.Pro126=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.254 in 1,612,602 control chromosomes in the GnomAD database, including 55,513 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.22 ( 4339 hom., cov: 32)

Exomes 𝑓: 0.26 ( 51174 hom. )

Consequence

POR
NM_001395413.1 synonymous

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9

Conservation

PhyloP100: -5.05

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=-0.91).

BP6

Variant 7-75980359-A-G is Benign according to our data. Variant chr7-75980359-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 256842.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-75980359-A-G is described in Lovd as [Benign].

BP7

Synonymous conserved (PhyloP=-5.05 with no splicing effect.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.443 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.378A>G	p.Pro126=	synonymous_variant	5/16	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.378A>G	p.Pro126=	synonymous_variant	5/16	1	NM_001395413.1	ENSP00000419970	P4

Frequencies

GnomAD3 genomes

AF:

0.216

AC:

32884

AN:

152028

Hom.:

4332

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0776

Gnomad AMI

AF:

0.168

Gnomad AMR

AF:

0.319

Gnomad ASJ

AF:

0.319

Gnomad EAS

AF:

0.458

Gnomad SAS

AF:

0.209

Gnomad FIN

AF:

0.210

Gnomad MID

AF:

0.357

Gnomad NFE

AF:

0.255

Gnomad OTH

AF:

0.234

GnomAD3 exomes

AF:

0.276

AC:

68491

AN:

248368

Hom.:

10812

AF XY:

0.269

AC XY:

36276

AN XY:

135008

show subpopulations

Gnomad AFR exome

AF:

0.0721

Gnomad AMR exome

AF:

0.421

Gnomad ASJ exome

AF:

0.313

Gnomad EAS exome

AF:

0.470

Gnomad SAS exome

AF:

0.206

Gnomad FIN exome

AF:

0.212

Gnomad NFE exome

AF:

0.256

Gnomad OTH exome

AF:

0.271

GnomAD4 exome

AF:

0.257

AC:

375938

AN:

1460456

Hom.:

51174

Cov.:

AF XY:

0.256

AC XY:

186175

AN XY:

726410

show subpopulations

Gnomad4 AFR exome

AF:

0.0706

Gnomad4 AMR exome

AF:

0.405

Gnomad4 ASJ exome

AF:

0.315

Gnomad4 EAS exome

AF:

0.457

Gnomad4 SAS exome

AF:

0.209

Gnomad4 FIN exome

AF:

0.209

Gnomad4 NFE exome

AF:

0.254

Gnomad4 OTH exome

AF:

0.259

GnomAD4 genome

AF:

0.216

AC:

32906

AN:

152146

Hom.:

4339

Cov.:

AF XY:

0.216

AC XY:

16082

AN XY:

74378

show subpopulations

Gnomad4 AFR

AF:

0.0774

Gnomad4 AMR

AF:

0.319

Gnomad4 ASJ

AF:

0.319

Gnomad4 EAS

AF:

0.458

Gnomad4 SAS

AF:

0.210

Gnomad4 FIN

AF:

0.210

Gnomad4 NFE

AF:

0.255

Gnomad4 OTH

AF:

0.239

Alfa

AF:

0.258

Hom.:

6261

Bravo

AF:

0.225

Asia WGS

AF:

0.322

AC:

1116

AN:

3478

EpiCase

AF:

0.264

EpiControl

AF:

0.254

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:3

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
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	-	- -

Congenital adrenal hyperplasia due to cytochrome P450 oxidoreductase deficiency

Benign:2

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	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -

not provided

Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Antley-Bixler syndrome with genital anomalies and disordered steroidogenesis

Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Oct 25, 2021

- -

Classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency

Benign:1

Likely 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

-0.91

CADD

Benign

0.040

DANN

Benign

0.37

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