rs28737229

Variant names:

• chr7-75907418-T-G
• rs28737229
• ENST00000453773.5:c.-14+8146T>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The ENST00000453773.5(POR):​c.-14+8146T>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.42 in 151,276 control chromosomes in the GnomAD database, including 13,865 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.42 (13865 hom., cov: 29)
• Consequence: POR ENST00000453773.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.168
• Publications: 6 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, STRONG Submitted by: ClinGen, PanelApp Australia, 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.81).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.458 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000453773.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
There are no transcript annotations for this variant.

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	POR	ENST00000453773.5	TSL:4	c.-14+8146T>G		intron	N/A	ENSP00000395813.2
	POR	ENST00000439963.5	TSL:4	c.-227T>G		upstream_gene	N/A	ENSP00000390540.2

Frequencies

GnomAD3 genomes AF: 0.420 AC: 63476 AN: 151162 Hom.: 13852 Cov.: 29

Gnomad AFR AF: 0.425

Gnomad AMI AF: 0.512

Gnomad AMR AF: 0.363

Gnomad ASJ AF: 0.387

Gnomad EAS AF: 0.0273

Gnomad SAS AF: 0.427

Gnomad FIN AF: 0.395

Gnomad MID AF: 0.401

Gnomad NFE AF: 0.463

Gnomad OTH AF: 0.428

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.420 AC: 63531 AN: 151276 Hom.: 13865 Cov.: 29 AF XY: 0.415 AC XY: 30660 AN XY: 73830

African (AFR) AF: 0.426 AC: 17559 AN: 41238

American (AMR) AF: 0.363 AC: 5494 AN: 15140

Ashkenazi Jewish (ASJ) AF: 0.387 AC: 1342 AN: 3466

East Asian (EAS) AF: 0.0272 AC: 140 AN: 5154

South Asian (SAS) AF: 0.426 AC: 2049 AN: 4806

European-Finnish (FIN) AF: 0.395 AC: 4083 AN: 10330

Middle Eastern (MID) AF: 0.398 AC: 117 AN: 294

European-Non Finnish (NFE) AF: 0.463 AC: 31383 AN: 67832

Other (OTH) AF: 0.426 AC: 899 AN: 2108

Alfa AF: 0.445 Hom.: 54820

Bravo AF: 0.413

Asia WGS AF: 0.227 AC: 792 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	1.8
DANN	Benign	0.55
PhyloP100		0.17
PromoterAI		0.024	Neutral

Splicing

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

Other links and lift over

dbSNP: rs28737229; hg19: chr7-75536736;