rs121912974

Variant names:

• chr7-75983548-G-C
• rs121912974
• NM_001395413.1:c.850G>C
• POR p.Ala284Pro

Your query was ambiguous. Multiple possible variants found:

• chr7-75983548-G-C
• chr7-75983548-G-A

Variant summary

Our verdict is Pathogenic. The variant received 14 ACMG points: 14P and 0B. PS3 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 (★★). ClinVar reports functional evidence for this variant: "SCV002195313: Experimental studies have shown that this missense change affects POR function (PMID:14758361, 18551037, 20940534, 21741353)." and additional evidence is available in ClinVar.

• 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:12 U:1 O:1
• Conservation: PhyloP100: 6.34
• Publications: 78 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: Ambry Genetics, ClinGen
• congenital adrenal hyperplasia due to cytochrome P450 oxidoreductase deficiency

  Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae)
• Antley-Bixler syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Pathogenic. The variant received 14 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV002195313: Experimental studies have shown that this missense change affects POR function (PMID: 14758361, 18551037, 20940534, 21741353).; SCV002768871: Functional assays have demonstrated that this variant causes significant reductions in enzyme activity and steroid biosynthesis (PMID: 27068427).; SCV000616830: 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)
• 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 VariationId is 16902.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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.850G>C	p.Ala284Pro	missense	Exon 9 of 16	NP_001382342.1	P16435
	POR	NM_001382655.3		c.904G>C	p.Ala302Pro	missense	Exon 10 of 17	NP_001369584.2
	POR	NM_001367562.3		c.850G>C	p.Ala284Pro	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.850G>C	p.Ala284Pro	missense	Exon 9 of 16	ENSP00000419970.2	P16435
	POR	ENST00000447222.5	TSL:5	c.1009G>C	p.Ala337Pro	missense	Exon 8 of 15	ENSP00000393527.1	H0Y4R2
	POR	ENST00000910548.1		c.850G>C	p.Ala284Pro	missense	Exon 9 of 16	ENSP00000580607.1

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

GnomAD2 exomes AF: 0.000241 AC: 60 AN: 249026 AF XY: 0.000252

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 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

African (AFR) AF: 0.0000299 AC: 1 AN: 33480

American (AMR) AF: 0.0000224 AC: 1 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.0000383 AC: 1 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: 0.000380 AC: 20 AN: 52624

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 0.000384 AC: 427 AN: 1111818

Other (OTH) AF: 0.000348 AC: 21 AN: 60360

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

African (AFR) AF: 0.0000483 AC: 2 AN: 41394

American (AMR) AF: 0.00 AC: 0 AN: 15264

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5182

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

European-Finnish (FIN) AF: 0.000378 AC: 4 AN: 10582

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.000382 AC: 26 AN: 68000

Other (OTH) AF: 0.00 AC: 0 AN: 2084

Alfa AF: 0.000447 Hom.: 0

Bravo AF: 0.000268

EpiCase AF: 0.000164

EpiControl AF: 0.000237

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
2	1	-	Antley-Bixler syndrome with genital anomalies and disordered steroidogenesis (3)
3	-	-	Congenital adrenal hyperplasia due to cytochrome P450 oxidoreductase deficiency (4)
2	-	-	not provided (2)
2	-	-	POR-related disorder (2)
1	-	-	Congenital adrenal hyperplasia due to cytochrome P450 oxidoreductase deficiency;C3150099:Antley-Bixler syndrome with genital anomalies and disordered steroidogenesis (1)
1	-	-	Differences in sex development (1)
1	-	-	Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
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
LIST_S2	Pathogenic	0.99	D
M_CAP	Uncertain	0.22	D
MetaRNN	Pathogenic	0.86	D
MetaSVM	Uncertain	0.73	D
PhyloP100		6.3
PrimateAI	Uncertain	0.70	T
PROVEAN	Uncertain	-3.6	D
REVEL	Pathogenic	0.89
Sift	Uncertain	0.0030	D
Sift4G	Uncertain	0.011	D
gMVP		0.96
Mutation Taster		=0/100	disease causing (ClinVar)

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs121912974;

hg19: chr7-75612866;