rs11540674

Variant names:

• chr7-75983587-G-A
• rs11540674
• NM_001395413.1:c.889G>A

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS2

The NM_001395413.1(POR):​c.889G>A​(p.Glu297Lys) variant causes a missense change. The variant allele was found at a frequency of 0.000387 in 1,613,054 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E297D) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00044 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00038 (4 hom.)
• Consequence: POR NM_001395413.1 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:3
• Conservation: PhyloP100: 5.57
• 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 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 -9 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.014287949).
• BP6: Variant 7-75983587-G-A is Benign according to our data. Variant chr7-75983587-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 909475.
• BS2: High Homozygotes in GnomAdExome4 at 4 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.889G>A	p.Glu297Lys	missense	Exon 9 of 16	NP_001382342.1	P16435
	POR	NM_001382655.3		c.943G>A	p.Glu315Lys	missense	Exon 10 of 17	NP_001369584.2
	POR	NM_001367562.3		c.889G>A	p.Glu297Lys	missense	Exon 10 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.889G>A	p.Glu297Lys	missense	Exon 9 of 16	ENSP00000419970.2	P16435
	POR	ENST00000447222.5	TSL:5	c.1048G>A	p.Glu350Lys	missense	Exon 8 of 15	ENSP00000393527.1	H0Y4R2
	POR	ENST00000910548.1		c.889G>A	p.Glu297Lys	missense	Exon 9 of 16	ENSP00000580607.1

Frequencies

GnomAD3 genomes AF: 0.000441 AC: 67 AN: 152030 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000242

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000197

Gnomad ASJ AF: 0.0147

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000147

Gnomad OTH AF: 0.000962

GnomAD2 exomes AF: 0.000739 AC: 184 AN: 249048 AF XY: 0.000725

Gnomad AFR exome AF: 0.000129

Gnomad AMR exome AF: 0.000261

Gnomad ASJ exome AF: 0.0137

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000222

Gnomad OTH exome AF: 0.00165

GnomAD4 exome AF: 0.000382 AC: 558 AN: 1460906 Hom.: 4 Cov.: 32 AF XY: 0.000377 AC XY: 274 AN XY: 726726

African (AFR) AF: 0.0000597 AC: 2 AN: 33478

American (AMR) AF: 0.000268 AC: 12 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.0146 AC: 382 AN: 26134

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.0000190 AC: 1 AN: 52654

Middle Eastern (MID) AF: 0.00260 AC: 15 AN: 5766

European-Non Finnish (NFE) AF: 0.0000872 AC: 97 AN: 1111834

Other (OTH) AF: 0.000812 AC: 49 AN: 60360

GnomAD4 genome AF: 0.000440 AC: 67 AN: 152148 Hom.: 0 Cov.: 33 AF XY: 0.000430 AC XY: 32 AN XY: 74380

African (AFR) AF: 0.0000241 AC: 1 AN: 41498

American (AMR) AF: 0.000196 AC: 3 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.0147 AC: 51 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5170

South Asian (SAS) AF: 0.00 AC: 0 AN: 4822

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10580

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000147 AC: 10 AN: 68018

Other (OTH) AF: 0.000951 AC: 2 AN: 2102

Alfa AF: 0.000763 Hom.: 5

Bravo AF: 0.000487

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00 AC: 0

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.00106 AC: 9

ExAC AF: 0.000479 AC: 58

EpiCase AF: 0.000436

EpiControl AF: 0.000296

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.20	T
BayesDel_noAF	Benign	-0.22
CADD	Uncertain	25
DANN	Uncertain	1.0
Eigen	Uncertain	0.32
Eigen_PC	Uncertain	0.37
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Uncertain	0.96	D
M_CAP	Benign	0.038	D
MetaRNN	Benign	0.014	T
MetaSVM	Benign	-0.70	T
PhyloP100		5.6
PrimateAI	Uncertain	0.70	T
PROVEAN	Uncertain	-2.6	D
REVEL	Benign	0.14
Sift	Uncertain	0.028	D
Sift4G	Uncertain	0.029	D
Vest4		0.56
MVP		0.82
MPC		0.13
ClinPred		0.048	T
GERP RS		4.0
gMVP		0.58
Mutation Taster		=90/10	polymorphism

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: rs11540674; hg19: chr7-75612905; COSMIC: COSV58694453; COSMIC: COSV58694453;