7-75915137-A-C

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 0P and 18B. BP4_Moderate BP6_Very_Strong BA1

The ENST00000706544.1(POR):c.-47A>C variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.437 in 154,052 control chromosomes in the GnomAD database, including 19,529 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.44 (19420 hom., cov: 33)
  • Exomes 𝑓: 0.31 (109 hom.)
• Consequence: POR ENST00000706544.1 5_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.320

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 -18 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.44).
• BP6: Variant 7-75915137-A-C is Benign according to our data. Variant chr7-75915137-A-C is described in ClinVar as [Benign]. Clinvar id is 360686.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-75915137-A-C is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.827 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
POR	NM_001395413.1			upstream_gene_variant		ENST00000461988.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
POR	ENST00000461988.6			upstream_gene_variant		1	NM_001395413.1	P4

Frequencies

GnomAD3 genomes AF: 0.438 AC: 66601 AN: 152044 Hom.: 19374 Cov.: 33

Gnomad AFR AF: 0.834

Gnomad AMI AF: 0.188

Gnomad AMR AF: 0.397

Gnomad ASJ AF: 0.246

Gnomad EAS AF: 0.265

Gnomad SAS AF: 0.345

Gnomad FIN AF: 0.243

Gnomad MID AF: 0.229

Gnomad NFE AF: 0.271

Gnomad OTH AF: 0.389

GnomAD4 exome AF: 0.308 AC: 584 AN: 1896 Hom.: 109 Cov.: 0 AF XY: 0.311 AC XY: 289 AN XY: 930

Gnomad4 AFR exome AF: 0.786

Gnomad4 AMR exome AF: 0.167

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.351

Gnomad4 NFE exome AF: 0.264

Gnomad4 OTH exome AF: 0.446

GnomAD4 genome AF: 0.438 AC: 66694 AN: 152156 Hom.: 19420 Cov.: 33 AF XY: 0.435 AC XY: 32322 AN XY: 74382

Gnomad4 AFR AF: 0.835

Gnomad4 AMR AF: 0.396

Gnomad4 ASJ AF: 0.246

Gnomad4 EAS AF: 0.265

Gnomad4 SAS AF: 0.343

Gnomad4 FIN AF: 0.243

Gnomad4 NFE AF: 0.271

Gnomad4 OTH AF: 0.386

Alfa AF: 0.377 Hom.: 3099

Bravo AF: 0.466

Asia WGS AF: 0.320 AC: 1111 AN: 3468

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

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

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 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. -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Mar 03, 2015

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.44
Cadd	Benign	16
Dann	Benign	0.88
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0

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: rs3823884; hg19: chr7-75544455; COSMIC: COSV67518579; COSMIC: COSV67518579;