7-75968227-C-T

Variant names:

• chr7-75968227-C-T
• rs10954724
• NM_001395413.1:c.180-4186C>T

Variant summary

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

The NM_001395413.1(POR):​c.180-4186C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.557 in 466,008 control chromosomes in the GnomAD database, including 73,656 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 0.54 (22244 hom., cov: 33)
  • Exomes 𝑓: 0.57 (51412 hom.)
• Consequence: POR NM_001395413.1 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.470
• Publications: 10 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=-0.79).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.596 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
POR	NM_001395413.1	c.180-4186C>T		intron_variant	Intron 2 of 15	ENST00000461988.6	NP_001382342.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
POR	ENST00000461988.6	c.180-4186C>T		intron_variant	Intron 2 of 15	1	NM_001395413.1	ENSP00000419970.2

Frequencies

GnomAD3 genomes AF: 0.536 AC: 81384 AN: 151966 Hom.: 22230 Cov.: 33

Gnomad AFR AF: 0.439

Gnomad AMI AF: 0.479

Gnomad AMR AF: 0.530

Gnomad ASJ AF: 0.631

Gnomad EAS AF: 0.465

Gnomad SAS AF: 0.530

Gnomad FIN AF: 0.506

Gnomad MID AF: 0.677

Gnomad NFE AF: 0.601

Gnomad OTH AF: 0.550

GnomAD2 exomes AF: 0.552 AC: 79451 AN: 143996 AF XY: 0.556

Gnomad AFR exome AF: 0.434

Gnomad AMR exome AF: 0.520

Gnomad ASJ exome AF: 0.619

Gnomad EAS exome AF: 0.473

Gnomad FIN exome AF: 0.509

Gnomad NFE exome AF: 0.602

Gnomad OTH exome AF: 0.570

GnomAD4 exome AF: 0.568 AC: 178339 AN: 313922 Hom.: 51412 Cov.: 0 AF XY: 0.567 AC XY: 100877 AN XY: 177798

African (AFR) AF: 0.443 AC: 3790 AN: 8562

American (AMR) AF: 0.520 AC: 14185 AN: 27276

Ashkenazi Jewish (ASJ) AF: 0.613 AC: 6613 AN: 10786

East Asian (EAS) AF: 0.465 AC: 4280 AN: 9214

South Asian (SAS) AF: 0.535 AC: 31919 AN: 59656

European-Finnish (FIN) AF: 0.508 AC: 12367 AN: 24354

Middle Eastern (MID) AF: 0.615 AC: 759 AN: 1234

European-Non Finnish (NFE) AF: 0.606 AC: 96177 AN: 158712

Other (OTH) AF: 0.584 AC: 8249 AN: 14128

GnomAD4 genome AF: 0.535 AC: 81441 AN: 152086 Hom.: 22244 Cov.: 33 AF XY: 0.528 AC XY: 39244 AN XY: 74352

African (AFR) AF: 0.439 AC: 18215 AN: 41504

American (AMR) AF: 0.529 AC: 8096 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.631 AC: 2189 AN: 3470

East Asian (EAS) AF: 0.465 AC: 2398 AN: 5156

South Asian (SAS) AF: 0.532 AC: 2564 AN: 4818

European-Finnish (FIN) AF: 0.506 AC: 5353 AN: 10580

Middle Eastern (MID) AF: 0.673 AC: 198 AN: 294

European-Non Finnish (NFE) AF: 0.601 AC: 40829 AN: 67956

Other (OTH) AF: 0.552 AC: 1164 AN: 2110

Alfa AF: 0.561 Hom.: 19527

Bravo AF: 0.536

Asia WGS AF: 0.480 AC: 1668 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.79
CADD	Benign	2.4
DANN	Benign	0.82
PhyloP100		-0.47
PromoterAI		-0.0050	Neutral
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: rs10954724; hg19: chr7-75597545; COSMIC: COSV67516125;