7-75985594-G-C

Variant names:

• chr7-75985594-G-C
• rs72557946
• NM_001395413.1:c.1405G>C

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_Strong BS1_Supporting BS2

The NM_001395413.1(POR):​c.1405G>C​(p.Val469Leu) variant causes a missense change. The variant allele was found at a frequency of 0.000271 in 1,562,518 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict 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. V469M) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00030 (0 hom., cov: 36)
  • Exomes 𝑓: 0.00027 (3 hom.)
• Consequence: POR NM_001395413.1 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4 B:2
• Conservation: PhyloP100: 5.04
• Publications: 7 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=0.029947221).
• BS1: Variant frequency is greater than expected in population mid. GnomAdExome4 allele frequency = 0.000268 (378/1410156) while in subpopulation MID AF = 0.00815 (45/5524). AF 95% confidence interval is 0.00626. There are 3 homozygotes in GnomAdExome4. There are 218 alleles in the male GnomAdExome4 subpopulation. Median coverage is 65. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High Homozygotes in GnomAdExome4 at 3 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.1405G>C	p.Val469Leu	missense	Exon 13 of 16	NP_001382342.1	P16435
	POR	NM_001382655.3		c.1459G>C	p.Val487Leu	missense	Exon 14 of 17	NP_001369584.2
	POR	NM_001367562.3		c.1405G>C	p.Val469Leu	missense	Exon 14 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.1405G>C	p.Val469Leu	missense	Exon 13 of 16	ENSP00000419970.2	P16435
	POR	ENST00000447222.5	TSL:5	c.1564G>C	p.Val522Leu	missense	Exon 12 of 15	ENSP00000393527.1	H0Y4R2
	POR	ENST00000910548.1		c.1405G>C	p.Val469Leu	missense	Exon 13 of 16	ENSP00000580607.1

Frequencies

GnomAD3 genomes AF: 0.000296 AC: 45 AN: 152244 Hom.: 0 Cov.: 36

Gnomad AFR AF: 0.000121

Gnomad AMI AF: 0.00329

Gnomad AMR AF: 0.00131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00124

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000147

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.000447 AC: 90 AN: 201346 AF XY: 0.000561

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000740

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000237

Gnomad OTH exome AF: 0.00119

GnomAD4 exome AF: 0.000268 AC: 378 AN: 1410156 Hom.: 3 Cov.: 65 AF XY: 0.000314 AC XY: 218 AN XY: 694058

African (AFR) AF: 0.0000305 AC: 1 AN: 32758

American (AMR) AF: 0.000651 AC: 27 AN: 41446

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 23316

East Asian (EAS) AF: 0.00 AC: 0 AN: 38632

South Asian (SAS) AF: 0.00183 AC: 143 AN: 78116

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 49388

Middle Eastern (MID) AF: 0.00815 AC: 45 AN: 5524

European-Non Finnish (NFE) AF: 0.000127 AC: 137 AN: 1082744

Other (OTH) AF: 0.000429 AC: 25 AN: 58232

GnomAD4 genome AF: 0.000295 AC: 45 AN: 152362 Hom.: 0 Cov.: 36 AF XY: 0.000309 AC XY: 23 AN XY: 74502

African (AFR) AF: 0.000120 AC: 5 AN: 41590

American (AMR) AF: 0.00131 AC: 20 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5174

South Asian (SAS) AF: 0.00124 AC: 6 AN: 4834

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10628

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

European-Non Finnish (NFE) AF: 0.000147 AC: 10 AN: 68038

Other (OTH) AF: 0.000473 AC: 1 AN: 2114

Alfa AF: 0.0000263 Hom.: 0

Bravo AF: 0.000502

ExAC AF: 0.000495 AC: 59

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	2	1	Congenital adrenal hyperplasia due to cytochrome P450 oxidoreductase deficiency (3)
-	1	-	not provided (1)
-	1	-	not specified (1)
-	-	1	POR-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.20
BayesDel_addAF	Benign	-0.38	T
BayesDel_noAF	Benign	-0.34
CADD	Benign	22
DANN	Benign	0.97
Eigen	Benign	-0.14
Eigen_PC	Benign	-0.072
FATHMM_MKL	Uncertain	0.87	D
LIST_S2	Benign	0.85	T
M_CAP	Uncertain	0.15	D
MetaRNN	Benign	0.030	T
MetaSVM	Benign	-0.60	T
PhyloP100		5.0
PrimateAI	Uncertain	0.76	T
PROVEAN	Benign	-1.8	N
REVEL	Benign	0.19
Sift	Benign	0.075	T
Sift4G	Benign	0.080	T
Vest4		0.52
MVP		0.83
MPC		0.13
ClinPred		0.045	T
GERP RS		3.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
gMVP		0.35
Mutation Taster		=75/25	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: rs72557946; hg19: chr7-75614912;