chr7-75960585-A-G

Variant names:

• chr7-75960585-A-G
• rs2868177
• NM_001395413.1:c.179+6405A>G

Variant summary

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

The NM_001395413.1(POR):​c.179+6405A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.366 in 151,890 control chromosomes in the GnomAD database, including 10,427 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 0.37 (10427 hom., cov: 31)
• Consequence: POR NM_001395413.1 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.323
• Publications: 31 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: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.92).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.432 is higher than 0.05.

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.179+6405A>G		intron	N/A	NP_001382342.1	P16435
	POR	NM_001382655.3		c.233+3624A>G		intron	N/A	NP_001369584.2
	POR	NM_001367562.3		c.179+6405A>G		intron	N/A	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.179+6405A>G		intron	N/A	ENSP00000419970.2	P16435
	POR	ENST00000447222.5	TSL:5	c.104+6405A>G		intron	N/A	ENSP00000393527.1	H0Y4R2
	POR	ENST00000910548.1		c.179+6405A>G		intron	N/A	ENSP00000580607.1

Frequencies

GnomAD3 genomes AF: 0.365 AC: 55447 AN: 151772 Hom.: 10404 Cov.: 31

Gnomad AFR AF: 0.419

Gnomad AMI AF: 0.254

Gnomad AMR AF: 0.406

Gnomad ASJ AF: 0.445

Gnomad EAS AF: 0.447

Gnomad SAS AF: 0.264

Gnomad FIN AF: 0.290

Gnomad MID AF: 0.475

Gnomad NFE AF: 0.333

Gnomad OTH AF: 0.361

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

GnomAD4 genome AF: 0.366 AC: 55518 AN: 151890 Hom.: 10427 Cov.: 31 AF XY: 0.361 AC XY: 26759 AN XY: 74226

African (AFR) AF: 0.419 AC: 17359 AN: 41406

American (AMR) AF: 0.406 AC: 6196 AN: 15252

Ashkenazi Jewish (ASJ) AF: 0.445 AC: 1545 AN: 3472

East Asian (EAS) AF: 0.447 AC: 2302 AN: 5148

South Asian (SAS) AF: 0.266 AC: 1280 AN: 4810

European-Finnish (FIN) AF: 0.290 AC: 3064 AN: 10554

Middle Eastern (MID) AF: 0.469 AC: 137 AN: 292

European-Non Finnish (NFE) AF: 0.333 AC: 22632 AN: 67936

Other (OTH) AF: 0.366 AC: 772 AN: 2112

Alfa AF: 0.352 Hom.: 21994

Bravo AF: 0.387

Asia WGS AF: 0.357 AC: 1241 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	3.1
DANN	Benign	0.53
PhyloP100		0.32
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: rs2868177; hg19: chr7-75589903;