rs121912974

chr7-75983548-G-C

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM2 PP3_Moderate PP5_Very_Strong

The NM_001395413.1(POR):c.850G>C(p.Ala284Pro) variant causes a missense change. The variant allele was found at a frequency of 0.000312 in 1,612,888 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★).

• Frequency:
  • Genomes: 𝑓 0.00021 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00032 (0 hom.)
• Consequence: POR NM_001395413.1 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:8 U:1 O:1
• Conservation: PhyloP100: 6.34

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]

ACMG classification

Verdict is Pathogenic. Variant got 12 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.858
• PP5: Variant 7-75983548-G-C is Pathogenic according to our data. Variant chr7-75983548-G-C is described in ClinVar as [Pathogenic]. Clinvar id is 16902.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-75983548-G-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
POR	NM_001395413.1	c.850G>C	p.Ala284Pro	missense_variant	9/16	ENST00000461988.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
POR	ENST00000461988.6	c.850G>C	p.Ala284Pro	missense_variant	9/16	1	NM_001395413.1	P4

Frequencies

GnomAD3 genomes AF: 0.000210 AC: 32 AN: 152026 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000483

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000378

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000382

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000241 AC: 60 AN: 249026 Hom.: 0 AF XY: 0.000252 AC XY: 34 AN XY: 135154

Gnomad AFR exome AF: 0.0000646

Gnomad AMR exome AF: 0.0000290

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.000603

Gnomad NFE exome AF: 0.000372

Gnomad OTH exome AF: 0.000496

GnomAD4 exome AF: 0.000322 AC: 471 AN: 1460862 Hom.: 0 Cov.: 32 AF XY: 0.000312 AC XY: 227 AN XY: 726700

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.0000224

Gnomad4 ASJ exome AF: 0.0000383

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.000380

Gnomad4 NFE exome AF: 0.000384

Gnomad4 OTH exome AF: 0.000348

GnomAD4 genome AF: 0.000210 AC: 32 AN: 152026 Hom.: 0 Cov.: 33 AF XY: 0.000148 AC XY: 11 AN XY: 74248

Gnomad4 AFR AF: 0.0000483

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000378

Gnomad4 NFE AF: 0.000382

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000447 Hom.: 0

Bravo AF: 0.000268

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000475 AC: 4

ExAC AF: 0.000223 AC: 27

EpiCase AF: 0.000164

EpiControl AF: 0.000237

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:8 Uncertain:1 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Congenital adrenal hyperplasia due to cytochrome P450 oxidoreductase deficiency Pathogenic:3 Other:1

Pathogenic, no assertion criteria provided	literature only	OMIM	May 01, 2005	- -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jan 07, 2024	This sequence change replaces alanine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 287 of the POR protein (p.Ala287Pro). This variant is present in population databases (rs121912974, gnomAD 0.05%). This missense change has been observed in individuals with POR deficiency (PMID: 14758361, 22162478). ClinVar contains an entry for this variant (Variation ID: 16902). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt POR protein function with a positive predictive value of 80%. Experimental studies have shown that this missense change affects POR function (PMID: 14758361, 18551037, 20940534, 21741353). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	Feb 02, 2022	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with Antley-Bixler syndrome with genital anomalies and disordered steroidogenesis (MIM#201750), and disordered steroidogenesis due to cytochrome P450 oxidoreductase (MIM#613571). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0200 - Variant is predicted to result in a missense amino acid change from alanine to proline. (I) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD (v2) <0.01 for a recessive condition (66 heterozygotes, 0 homozygotes). (SP) 0502 - Missense variant with conflicting in silico predictions and uninformative conservation. (I) 0600 - Variant is located in the annotated FAD-binding FR-type domain (Uniprot). (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been reported as pathogenic, and has been observed in many homozygous and compound heterozygous patients with P450 oxidoreductase deficiency. It is regarded as the most common variant in Caucasian populations, and results in a mild-moderate form of disease (ClinVar, PMID: 27068427, PMID: 22162478). (SP) 1002 - This variant has moderate functional evidence supporting abnormal protein function. Functional assays have demonstrated that this variant causes significant reductions in enzyme activity and steroid biosynthesis (PMID: 27068427). (SP) 1205 - This variant has been shown to be maternally inherited. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -
not provided, no classification provided	literature only	GeneReviews	-	- -

Antley-Bixler syndrome with genital anomalies and disordered steroidogenesis Pathogenic:2 Uncertain:1

Pathogenic, no assertion criteria provided	literature only	OMIM	May 01, 2005	- -
Uncertain significance, no assertion criteria provided	research	Lupski Lab, Baylor-Hopkins CMG, Baylor College of Medicine	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein	Jan 12, 2023	ACMG classification criteria: PS3 supporting, PM3 very strong, PP3 supporting -

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Nov 21, 2022	Published functional studies demonstrate a decreased rate of flavin reduction and conformational protein instability leading to proteolytic susceptibility (Jin et al., 2015; McCammon et al., 2016); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 21741353, 20732302, 22252407, 19621255, 15793702, 17389698, 19837910, 17505056, 17635179, 16495354, 17062779, 25728647, 18551037, 20697309, 20940534, 22547083, 22719896, 14758361, 26969897, 26670660, 27496950, 18259105, 12116245, 15220035, 31230720, 31837199, 31980526, 32242900, 34426522, 31589614, 31128914, 35842891, 22162478, 21190981) -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Oct 04, 2020	- -

POR-related disorder Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Daryl Scott Lab, Baylor College of Medicine

Feb 01, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.21	D
BayesDel_noAF	Pathogenic	0.40
Cadd	Pathogenic	30
Dann	Uncertain	1.0
Eigen	Uncertain	0.63
Eigen_PC	Uncertain	0.61
FATHMM_MKL	Uncertain	0.91	D
M_CAP	Uncertain	0.22	D
MetaRNN	Pathogenic	0.86	D;D;D
MetaSVM	Uncertain	0.73	D
MutationTaster	Benign	1.0	A;A;A;A;A;A
PrimateAI	Uncertain	0.70	T
PROVEAN	Uncertain	-3.6	D;D;D
REVEL	Pathogenic	0.89
Sift	Uncertain	0.0030	D;D;D
Sift4G	Uncertain	0.011	D;D;D
Vest4		0.75
MVP		0.94
MPC		0.59
ClinPred		0.83	D
GERP RS		5.2
gMVP		0.96

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.080		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs121912974; hg19: chr7-75612866;