rs72557954

Variant names:

• chr7-75986163-A-G
• rs72557954
• NM_001395413.1:c.1811A>G

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PP3_Moderate PP5_Very_Strong

The NM_001395413.1(POR):​c.1811A>G​(p.Tyr604Cys) variant causes a missense change. The variant allele was found at a frequency of 0.0000745 in 1,610,516 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 Likely pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. Y604Y) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.000020 (0 hom., cov: 34)
  • Exomes 𝑓: 0.000080 (0 hom.)
• Consequence: POR NM_001395413.1 missense
• Clinical Significance: Likely pathogenic criteria provided, multiple submitters, no conflicts P:5
• Conservation: PhyloP100: 4.60
• Publications: 14 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: Pathogenic. The variant received 10 ACMG points.

• PP3: MetaRNN computational evidence supports a deleterious effect, 0.912
• PP5: Variant 7-75986163-A-G is Pathogenic according to our data. Variant chr7-75986163-A-G is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 1254698.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.1811A>G	p.Tyr604Cys	missense	Exon 15 of 16	NP_001382342.1	P16435
	POR	NM_001382655.3		c.1865A>G	p.Tyr622Cys	missense	Exon 16 of 17	NP_001369584.2
	POR	NM_001367562.3		c.1811A>G	p.Tyr604Cys	missense	Exon 16 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.1811A>G	p.Tyr604Cys	missense	Exon 15 of 16	ENSP00000419970.2	P16435
	POR	ENST00000447222.5	TSL:5	c.1970A>G	p.Tyr657Cys	missense	Exon 14 of 15	ENSP00000393527.1	H0Y4R2
	POR	ENST00000910548.1		c.1811A>G	p.Tyr604Cys	missense	Exon 15 of 16	ENSP00000580607.1

Frequencies

GnomAD3 genomes AF: 0.0000197 AC: 3 AN: 152210 Hom.: 0 Cov.: 34

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000110 AC: 27 AN: 244454 AF XY: 0.000113

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000293

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000469

Gnomad NFE exome AF: 0.0000906

Gnomad OTH exome AF: 0.000168

GnomAD4 exome AF: 0.0000802 AC: 117 AN: 1458306 Hom.: 0 Cov.: 34 AF XY: 0.0000800 AC XY: 58 AN XY: 725162

African (AFR) AF: 0.0000897 AC: 3 AN: 33442

American (AMR) AF: 0.0000675 AC: 3 AN: 44416

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26038

East Asian (EAS) AF: 0.000479 AC: 19 AN: 39640

South Asian (SAS) AF: 0.000303 AC: 26 AN: 85884

European-Finnish (FIN) AF: 0.0000192 AC: 1 AN: 51980

Middle Eastern (MID) AF: 0.000347 AC: 2 AN: 5764

European-Non Finnish (NFE) AF: 0.0000522 AC: 58 AN: 1110858

Other (OTH) AF: 0.0000829 AC: 5 AN: 60284

GnomAD4 genome AF: 0.0000197 AC: 3 AN: 152210 Hom.: 0 Cov.: 34 AF XY: 0.0000134 AC XY: 1 AN XY: 74350

African (AFR) AF: 0.00 AC: 0 AN: 41460

American (AMR) AF: 0.00 AC: 0 AN: 15294

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5166

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4834

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10626

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

European-Non Finnish (NFE) AF: 0.0000294 AC: 2 AN: 68038

Other (OTH) AF: 0.00 AC: 0 AN: 2094

Alfa AF: 0.0000823 Hom.: 0

Bravo AF: 0.0000264

ExAC AF: 0.000124 AC: 15

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

ClinVar submissions

Significance: Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
1	-	-	Congenital adrenal hyperplasia (1)
1	-	-	Congenital adrenal hyperplasia due to cytochrome P450 oxidoreductase deficiency (1)
1	-	-	Congenital adrenal hyperplasia due to cytochrome P450 oxidoreductase deficiency;C2936791:Antley-Bixler syndrome without genital anomalies or disordered steroidogenesis;C3150099:Antley-Bixler syndrome with genital anomalies and disordered steroidogenesis (1)
1	-	-	Congenital adrenal hyperplasia due to cytochrome P450 oxidoreductase deficiency;C3150099:Antley-Bixler syndrome with genital anomalies and disordered steroidogenesis (1)
1	-	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.96
BayesDel_addAF	Uncertain	0.034	T
BayesDel_noAF	Pathogenic	0.14
CADD	Pathogenic	27
DANN	Uncertain	1.0
Eigen	Pathogenic	0.72
Eigen_PC	Uncertain	0.50
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Pathogenic	0.99	D
M_CAP	Pathogenic	0.61	D
MetaRNN	Pathogenic	0.91	D
MetaSVM	Pathogenic	0.88	D
PhyloP100		4.6
PrimateAI	Uncertain	0.76	T
PROVEAN	Pathogenic	-7.6	D
REVEL	Pathogenic	0.75
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Vest4		0.75
MVP		0.89
MPC		0.61
ClinPred		0.97	D
GERP RS		3.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
gMVP		0.88
Mutation Taster		=5/95	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs72557954; hg19: chr7-75615481;