rs2302429

Positions:

• chr7-75985459-G-A

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.1390-120G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.188 in 1,290,564 control chromosomes in the GnomAD database, including 24,631 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.18 (2853 hom., cov: 35)
  • Exomes 𝑓: 0.19 (21778 hom.)
• Consequence: POR NM_001395413.1 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 2.48

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=-0.84).
• BP6: Variant 7-75985459-G-A is Benign according to our data. Variant chr7-75985459-G-A is described in ClinVar as [Benign]. Clinvar id is 1282569.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.272 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
POR	NM_001395413.1	c.1390-120G>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.1390-120G>A		intron_variant		1	NM_001395413.1	ENSP00000419970	P4

Frequencies

GnomAD3 genomes AF: 0.177 AC: 26937 AN: 152134 Hom.: 2850 Cov.: 35

Gnomad AFR AF: 0.0860

Gnomad AMI AF: 0.0373

Gnomad AMR AF: 0.220

Gnomad ASJ AF: 0.165

Gnomad EAS AF: 0.284

Gnomad SAS AF: 0.198

Gnomad FIN AF: 0.358

Gnomad MID AF: 0.108

Gnomad NFE AF: 0.188

Gnomad OTH AF: 0.174

GnomAD4 exome AF: 0.190 AC: 215949 AN: 1138314 Hom.: 21778 Cov.: 17 AF XY: 0.190 AC XY: 105348 AN XY: 554320

Gnomad4 AFR exome AF: 0.0812

Gnomad4 AMR exome AF: 0.218

Gnomad4 ASJ exome AF: 0.166

Gnomad4 EAS exome AF: 0.298

Gnomad4 SAS exome AF: 0.189

Gnomad4 FIN exome AF: 0.344

Gnomad4 NFE exome AF: 0.183

Gnomad4 OTH exome AF: 0.188

GnomAD4 genome AF: 0.177 AC: 26935 AN: 152250 Hom.: 2853 Cov.: 35 AF XY: 0.187 AC XY: 13881 AN XY: 74424

Gnomad4 AFR AF: 0.0857

Gnomad4 AMR AF: 0.220

Gnomad4 ASJ AF: 0.165

Gnomad4 EAS AF: 0.284

Gnomad4 SAS AF: 0.197

Gnomad4 FIN AF: 0.358

Gnomad4 NFE AF: 0.188

Gnomad4 OTH AF: 0.172

Alfa AF: 0.186 Hom.: 315

Bravo AF: 0.162

Asia WGS AF: 0.217 AC: 754 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 26, 2018	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	5.4
DANN	Benign	0.48

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.19		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: rs2302429; hg19: chr7-75614777;