rs10280802

Variant names:

• chr7-75899819-C-T
• rs10280802
• ENST00000453773.5:c.-14+547C>T

Variant summary

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

The ENST00000453773.5(POR):​c.-14+547C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.198 in 152,088 control chromosomes in the GnomAD database, including 3,135 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 0.20 (3135 hom., cov: 32)
• Consequence: POR ENST00000453773.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.272
• 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, 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=-0.98).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.221 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
POR	ENST00000453773.5	c.-14+547C>T		intron_variant	Intron 1 of 4	4		ENSP00000395813.2

Frequencies

GnomAD3 genomes AF: 0.198 AC: 30095 AN: 151970 Hom.: 3134 Cov.: 32

Gnomad AFR AF: 0.189

Gnomad AMI AF: 0.251

Gnomad AMR AF: 0.174

Gnomad ASJ AF: 0.186

Gnomad EAS AF: 0.0166

Gnomad SAS AF: 0.191

Gnomad FIN AF: 0.184

Gnomad MID AF: 0.277

Gnomad NFE AF: 0.224

Gnomad OTH AF: 0.212

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

GnomAD4 genome AF: 0.198 AC: 30123 AN: 152088 Hom.: 3135 Cov.: 32 AF XY: 0.195 AC XY: 14475 AN XY: 74342

African (AFR) AF: 0.189 AC: 7862 AN: 41500

American (AMR) AF: 0.174 AC: 2646 AN: 15250

Ashkenazi Jewish (ASJ) AF: 0.186 AC: 645 AN: 3470

East Asian (EAS) AF: 0.0166 AC: 86 AN: 5180

South Asian (SAS) AF: 0.193 AC: 928 AN: 4818

European-Finnish (FIN) AF: 0.184 AC: 1953 AN: 10596

Middle Eastern (MID) AF: 0.274 AC: 80 AN: 292

European-Non Finnish (NFE) AF: 0.224 AC: 15253 AN: 67970

Other (OTH) AF: 0.210 AC: 443 AN: 2108

Alfa AF: 0.214 Hom.: 11272

Bravo AF: 0.195

Asia WGS AF: 0.106 AC: 370 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.98
CADD	Benign	0.72
DANN	Benign	0.45
PhyloP100		-0.27

Splicing

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

Other links and lift over

dbSNP: rs10280802; hg19: chr7-75529137;