rs17853284

Variant names:

• chr7-75981558-C-T
• rs17853284
• NM_001395413.1:c.674C>T

Your query was ambiguous. Multiple possible variants found:

• chr7-75981558-C-T
• chr7-75981558-C-A

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_001395413.1(POR):​c.674C>T​(p.Pro225Leu) variant causes a missense change. The variant allele was found at a frequency of 0.0035 in 1,613,044 control chromosomes in the GnomAD database, including 13 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. P225P) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0026 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0036 (13 hom.)
• Consequence: POR NM_001395413.1 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:5 B:5
• Conservation: PhyloP100: 5.86
• Publications: 34 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 Submitted by: ClinGen, 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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.038654447).
• BP6: Variant 7-75981558-C-T is Benign according to our data. Variant chr7-75981558-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 436385.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00257 (392/152314) while in subpopulation NFE AF = 0.00425 (289/68018). AF 95% confidence interval is 0.00385. There are 0 homozygotes in GnomAd4. There are 168 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 13 AR,AD gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001395413.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	POR	NM_001395413.1	MANE Select	c.674C>T	p.Pro225Leu	missense	Exon 7 of 16	NP_001382342.1	P16435
	POR	NM_001382655.3		c.728C>T	p.Pro243Leu	missense	Exon 8 of 17	NP_001369584.2
	POR	NM_001367562.3		c.674C>T	p.Pro225Leu	missense	Exon 8 of 17	NP_001354491.2	P16435

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	POR	ENST00000461988.6	TSL:1 MANE Select	c.674C>T	p.Pro225Leu	missense	Exon 7 of 16	ENSP00000419970.2	P16435
	POR	ENST00000447222.5	TSL:5	c.833C>T	p.Pro278Leu	missense	Exon 6 of 15	ENSP00000393527.1	H0Y4R2
	POR	ENST00000910548.1		c.674C>T	p.Pro225Leu	missense	Exon 7 of 16	ENSP00000580607.1

Frequencies

GnomAD3 genomes AF: 0.00258 AC: 392 AN: 152196 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000796

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00242

Gnomad ASJ AF: 0.00288

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00151

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.00425

Gnomad OTH AF: 0.000955

GnomAD2 exomes AF: 0.00248 AC: 610 AN: 245926 AF XY: 0.00243

Gnomad AFR exome AF: 0.000929

Gnomad AMR exome AF: 0.000758

Gnomad ASJ exome AF: 0.00131

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00209

Gnomad NFE exome AF: 0.00443

Gnomad OTH exome AF: 0.00235

GnomAD4 exome AF: 0.00360 AC: 5258 AN: 1460730 Hom.: 13 Cov.: 32 AF XY: 0.00356 AC XY: 2587 AN XY: 726612

African (AFR) AF: 0.000598 AC: 20 AN: 33468

American (AMR) AF: 0.000851 AC: 38 AN: 44658

Ashkenazi Jewish (ASJ) AF: 0.00184 AC: 48 AN: 26102

East Asian (EAS) AF: 0.0000504 AC: 2 AN: 39688

South Asian (SAS) AF: 0.000267 AC: 23 AN: 86144

European-Finnish (FIN) AF: 0.00229 AC: 121 AN: 52886

Middle Eastern (MID) AF: 0.00173 AC: 10 AN: 5766

European-Non Finnish (NFE) AF: 0.00437 AC: 4857 AN: 1111672

Other (OTH) AF: 0.00230 AC: 139 AN: 60346

GnomAD4 genome AF: 0.00257 AC: 392 AN: 152314 Hom.: 0 Cov.: 33 AF XY: 0.00226 AC XY: 168 AN XY: 74486

African (AFR) AF: 0.000794 AC: 33 AN: 41584

American (AMR) AF: 0.00242 AC: 37 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.00288 AC: 10 AN: 3470

East Asian (EAS) AF: 0.000194 AC: 1 AN: 5166

South Asian (SAS) AF: 0.000414 AC: 2 AN: 4832

European-Finnish (FIN) AF: 0.00151 AC: 16 AN: 10620

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.00425 AC: 289 AN: 68018

Other (OTH) AF: 0.000945 AC: 2 AN: 2116

Alfa AF: 0.00360 Hom.: 3

Bravo AF: 0.00247

TwinsUK AF: 0.00405 AC: 15

ALSPAC AF: 0.00519 AC: 20

ESP6500AA AF: 0.000738 AC: 3

ESP6500EA AF: 0.00478 AC: 40

ExAC AF: 0.00265 AC: 320

EpiCase AF: 0.00365

EpiControl AF: 0.00380

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	3	1	not provided (4)
-	1	1	Congenital adrenal hyperplasia due to cytochrome P450 oxidoreductase deficiency (2)
-	1	1	not specified (2)
-	-	1	Antley-Bixler syndrome with genital anomalies and disordered steroidogenesis (1)
-	-	1	POR-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.52
BayesDel_addAF	Uncertain	0.088	D
BayesDel_noAF	Pathogenic	0.35
CADD	Pathogenic	26
DANN	Uncertain	1.0
Eigen	Uncertain	0.47
Eigen_PC	Uncertain	0.41
FATHMM_MKL	Uncertain	0.95	D
M_CAP	Pathogenic	0.32	D
MetaRNN	Benign	0.039	T
MetaSVM	Uncertain	0.36	D
PhyloP100		5.9
PrimateAI	Uncertain	0.78	T
PROVEAN	Pathogenic	-8.6	D
REVEL	Uncertain	0.55
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.049	D
Vest4		0.88
MVP		0.88
MPC		0.40
ClinPred		0.070	T
GERP RS		3.7
PromoterAI		0.021	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
gMVP		0.62
Mutation Taster		=15/85	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
Splicevardb		2.0
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: rs17853284; hg19: chr7-75610876; COSMIC: COSV67517788; COSMIC: COSV67517788;