rs41301427

Variant names:

• chr7-75985239-G-A
• rs41301427
• NM_001395413.1:c.1389+32G>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001395413.1(POR):​c.1389+32G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.093 in 1,557,518 control chromosomes in the GnomAD database, including 7,427 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.074 (538 hom., cov: 33)
  • Exomes 𝑓: 0.095 (6889 hom.)
• Consequence: POR NM_001395413.1 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.457
• Publications: 11 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.133 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
POR	NM_001395413.1	c.1389+32G>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.1389+32G>A		intron_variant	Intron 12 of 15	1	NM_001395413.1	ENSP00000419970.2

Frequencies

GnomAD3 genomes AF: 0.0741 AC: 11284 AN: 152178 Hom.: 537 Cov.: 33

Gnomad AFR AF: 0.0427

Gnomad AMI AF: 0.305

Gnomad AMR AF: 0.0586

Gnomad ASJ AF: 0.0844

Gnomad EAS AF: 0.0266

Gnomad SAS AF: 0.142

Gnomad FIN AF: 0.0442

Gnomad MID AF: 0.104

Gnomad NFE AF: 0.0962

Gnomad OTH AF: 0.0842

GnomAD2 exomes AF: 0.0850 AC: 16056 AN: 188896 AF XY: 0.0916

Gnomad AFR exome AF: 0.0416

Gnomad AMR exome AF: 0.0463

Gnomad ASJ exome AF: 0.0873

Gnomad EAS exome AF: 0.0284

Gnomad FIN exome AF: 0.0544

Gnomad NFE exome AF: 0.0980

Gnomad OTH exome AF: 0.0828

GnomAD4 exome AF: 0.0951 AC: 133606 AN: 1405222 Hom.: 6889 Cov.: 35 AF XY: 0.0971 AC XY: 67393 AN XY: 693800

African (AFR) AF: 0.0413 AC: 1353 AN: 32744

American (AMR) AF: 0.0479 AC: 1983 AN: 41356

Ashkenazi Jewish (ASJ) AF: 0.0873 AC: 2118 AN: 24270

East Asian (EAS) AF: 0.0183 AC: 704 AN: 38438

South Asian (SAS) AF: 0.147 AC: 11953 AN: 81578

European-Finnish (FIN) AF: 0.0522 AC: 1929 AN: 36926

Middle Eastern (MID) AF: 0.128 AC: 720 AN: 5642

European-Non Finnish (NFE) AF: 0.0993 AC: 107809 AN: 1085898

Other (OTH) AF: 0.0863 AC: 5037 AN: 58370

GnomAD4 genome AF: 0.0742 AC: 11296 AN: 152296 Hom.: 538 Cov.: 33 AF XY: 0.0733 AC XY: 5458 AN XY: 74480

African (AFR) AF: 0.0427 AC: 1775 AN: 41570

American (AMR) AF: 0.0584 AC: 894 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.0844 AC: 293 AN: 3472

East Asian (EAS) AF: 0.0267 AC: 138 AN: 5174

South Asian (SAS) AF: 0.142 AC: 686 AN: 4828

European-Finnish (FIN) AF: 0.0442 AC: 470 AN: 10624

Middle Eastern (MID) AF: 0.119 AC: 35 AN: 294

European-Non Finnish (NFE) AF: 0.0962 AC: 6543 AN: 68010

Other (OTH) AF: 0.0871 AC: 184 AN: 2112

Alfa AF: 0.0833 Hom.: 109

Bravo AF: 0.0716

Asia WGS AF: 0.0730 AC: 255 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	1.9
DANN	Benign	0.87
PhyloP100		0.46
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs41301427; hg19: chr7-75614557; COSMIC: COSV58693536; COSMIC: COSV58693536;