7-75959386-A-G

Variant names:

• chr7-75959386-A-G
• rs12537277
• NM_001395413.1:c.179+5206A>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+5206A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.69 in 151,974 control chromosomes in the GnomAD database, including 36,441 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 0.69 (36441 hom., cov: 32)
• Consequence: POR NM_001395413.1 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.100
• Publications: 1 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=-1.01).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.758 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	POR	NM_001395413.1	MANE Select	c.179+5206A>G		intron	N/A	NP_001382342.1
	POR	NM_001382655.3		c.233+2425A>G		intron	N/A	NP_001369584.2
	POR	NM_001367562.3		c.179+5206A>G		intron	N/A	NP_001354491.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	POR	ENST00000461988.6	TSL:1 MANE Select	c.179+5206A>G		intron	N/A	ENSP00000419970.2
	POR	ENST00000447222.5	TSL:5	c.104+5206A>G		intron	N/A	ENSP00000393527.1
	POR	ENST00000706545.1		c.188+5206A>G		intron	N/A	ENSP00000516443.1

Frequencies

GnomAD3 genomes AF: 0.690 AC: 104810 AN: 151854 Hom.: 36394 Cov.: 32

Gnomad AFR AF: 0.622

Gnomad AMI AF: 0.771

Gnomad AMR AF: 0.706

Gnomad ASJ AF: 0.741

Gnomad EAS AF: 0.777

Gnomad SAS AF: 0.604

Gnomad FIN AF: 0.773

Gnomad MID AF: 0.759

Gnomad NFE AF: 0.711

Gnomad OTH AF: 0.696

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

GnomAD4 genome AF: 0.690 AC: 104914 AN: 151974 Hom.: 36441 Cov.: 32 AF XY: 0.691 AC XY: 51336 AN XY: 74278

African (AFR) AF: 0.622 AC: 25760 AN: 41402

American (AMR) AF: 0.706 AC: 10783 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.741 AC: 2573 AN: 3470

East Asian (EAS) AF: 0.778 AC: 4018 AN: 5166

South Asian (SAS) AF: 0.604 AC: 2910 AN: 4816

European-Finnish (FIN) AF: 0.773 AC: 8170 AN: 10576

Middle Eastern (MID) AF: 0.759 AC: 223 AN: 294

European-Non Finnish (NFE) AF: 0.711 AC: 48297 AN: 67950

Other (OTH) AF: 0.699 AC: 1477 AN: 2114

Alfa AF: 0.709 Hom.: 99867

Bravo AF: 0.691

Asia WGS AF: 0.689 AC: 2396 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-1.0
CADD	Benign	2.2
DANN	Benign	0.69
PhyloP100		0.10
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: rs12537277; hg19: chr7-75588704;