rs2302429

Variant names:

• chr7-75985459-G-A
• rs2302429
• NM_001395413.1:c.1390-120G>A

Variant summary

Our verdict is Benign. The variant received -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
• Publications: 13 publications found

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 Gene-Disease associations (from GenCC):

• Antley-Bixler syndrome with genital anomalies and disordered steroidogenesis

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: ClinGen, PanelApp Australia, Ambry Genetics
• congenital adrenal hyperplasia due to cytochrome P450 oxidoreductase deficiency

  Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet
• Antley-Bixler syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -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 VariationId 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 rank	MANE	Protein	UniProt
POR	NM_001395413.1	c.1390-120G>A		intron_variant	Intron 12 of 15	ENST00000461988.6	NP_001382342.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
POR	ENST00000461988.6	c.1390-120G>A		intron_variant	Intron 12 of 15	1	NM_001395413.1	ENSP00000419970.2

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

African (AFR) AF: 0.0812 AC: 2092 AN: 25776

American (AMR) AF: 0.218 AC: 4111 AN: 18834

Ashkenazi Jewish (ASJ) AF: 0.166 AC: 2956 AN: 17848

East Asian (EAS) AF: 0.298 AC: 9997 AN: 33528

South Asian (SAS) AF: 0.189 AC: 10665 AN: 56336

European-Finnish (FIN) AF: 0.344 AC: 12561 AN: 36546

Middle Eastern (MID) AF: 0.167 AC: 556 AN: 3336

European-Non Finnish (NFE) AF: 0.183 AC: 163962 AN: 897874

Other (OTH) AF: 0.188 AC: 9049 AN: 48236

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

African (AFR) AF: 0.0857 AC: 3565 AN: 41582

American (AMR) AF: 0.220 AC: 3363 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.165 AC: 572 AN: 3468

East Asian (EAS) AF: 0.284 AC: 1468 AN: 5164

South Asian (SAS) AF: 0.197 AC: 952 AN: 4830

European-Finnish (FIN) AF: 0.358 AC: 3785 AN: 10584

Middle Eastern (MID) AF: 0.102 AC: 30 AN: 294

European-Non Finnish (NFE) AF: 0.188 AC: 12803 AN: 68006

Other (OTH) AF: 0.172 AC: 363 AN: 2114

Alfa AF: 0.182 Hom.: 319

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

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Jun 26, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	5.4
DANN	Benign	0.48
PhyloP100		2.5
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs2302429; hg19: chr7-75614777;