rs2286823

Positions:

• chr7-75984978-G-A
• chr7-75984978-G-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001395413.1(POR):​c.1239+20G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.298 in 1,572,946 control chromosomes in the GnomAD database, including 71,928 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.28 (5970 hom., cov: 32)
  • Exomes 𝑓: 0.30 (65958 hom.)
• Consequence: POR NM_001395413.1 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: -0.143

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]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.89).
• BP6: Variant 7-75984978-G-A is Benign according to our data. Variant chr7-75984978-G-A is described in ClinVar as [Benign]. Clinvar id is 256839.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-75984978-G-A is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.407 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
POR	NM_001395413.1	c.1239+20G>A		intron_variant		ENST00000461988.6	NP_001382342.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
POR	ENST00000461988.6	c.1239+20G>A		intron_variant		1	NM_001395413.1	ENSP00000419970	P4

Frequencies

GnomAD3 genomes AF: 0.275 AC: 41614 AN: 151246 Hom.: 5961 Cov.: 32

Gnomad AFR AF: 0.203

Gnomad AMI AF: 0.230

Gnomad AMR AF: 0.306

Gnomad ASJ AF: 0.434

Gnomad EAS AF: 0.421

Gnomad SAS AF: 0.238

Gnomad FIN AF: 0.238

Gnomad MID AF: 0.446

Gnomad NFE AF: 0.301

Gnomad OTH AF: 0.288

GnomAD3 exomes AF: 0.309 AC: 67880 AN: 219986 Hom.: 10826 AF XY: 0.304 AC XY: 36519 AN XY: 120040

Gnomad AFR exome AF: 0.201

Gnomad AMR exome AF: 0.364

Gnomad ASJ exome AF: 0.423

Gnomad EAS exome AF: 0.430

Gnomad SAS exome AF: 0.246

Gnomad FIN exome AF: 0.233

Gnomad NFE exome AF: 0.303

Gnomad OTH exome AF: 0.315

GnomAD4 exome AF: 0.301 AC: 427373 AN: 1421582 Hom.: 65958 Cov.: 43 AF XY: 0.300 AC XY: 210536 AN XY: 702378

Gnomad4 AFR exome AF: 0.200

Gnomad4 AMR exome AF: 0.360

Gnomad4 ASJ exome AF: 0.428

Gnomad4 EAS exome AF: 0.412

Gnomad4 SAS exome AF: 0.248

Gnomad4 FIN exome AF: 0.230

Gnomad4 NFE exome AF: 0.301

Gnomad4 OTH exome AF: 0.312

GnomAD4 genome AF: 0.275 AC: 41649 AN: 151364 Hom.: 5970 Cov.: 32 AF XY: 0.272 AC XY: 20108 AN XY: 73942

Gnomad4 AFR AF: 0.203

Gnomad4 AMR AF: 0.306

Gnomad4 ASJ AF: 0.434

Gnomad4 EAS AF: 0.421

Gnomad4 SAS AF: 0.240

Gnomad4 FIN AF: 0.238

Gnomad4 NFE AF: 0.301

Gnomad4 OTH AF: 0.293

Alfa AF: 0.277 Hom.: 607

Bravo AF: 0.285

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

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

not provided Benign:2

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

Congenital adrenal hyperplasia due to cytochrome P450 oxidoreductase deficiency Benign:1

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

-

This variant is intronic -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	1.1
DANN	Benign	0.44

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

Other links and lift over

dbSNP: rs2286823; hg19: chr7-75614296; COSMIC: COSV58694823; COSMIC: COSV58694823;