NM_001395413.1:c.179+3038T>C

Variant names:

• chr7-75957218-T-C
• rs4728533
• NM_001395413.1:c.179+3038T>C

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+3038T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.789 in 151,974 control chromosomes in the GnomAD database, including 49,291 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 0.79 (49291 hom., cov: 30)
• Consequence: POR NM_001395413.1 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.03
• Publications: 8 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=-0.9).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.9 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+3038T>C		intron	N/A	NP_001382342.1
	POR	NM_001382655.3		c.233+257T>C		intron	N/A	NP_001369584.2
	POR	NM_001367562.3		c.179+3038T>C		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+3038T>C		intron	N/A	ENSP00000419970.2
	POR	ENST00000447222.5	TSL:5	c.104+3038T>C		intron	N/A	ENSP00000393527.1
	POR	ENST00000706545.1		c.188+3038T>C		intron	N/A	ENSP00000516443.1

Frequencies

GnomAD3 genomes AF: 0.789 AC: 119873 AN: 151858 Hom.: 49263 Cov.: 30

Gnomad AFR AF: 0.547

Gnomad AMI AF: 0.907

Gnomad AMR AF: 0.776

Gnomad ASJ AF: 0.889

Gnomad EAS AF: 0.754

Gnomad SAS AF: 0.844

Gnomad FIN AF: 0.946

Gnomad MID AF: 0.902

Gnomad NFE AF: 0.906

Gnomad OTH AF: 0.823

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

GnomAD4 genome AF: 0.789 AC: 119954 AN: 151974 Hom.: 49291 Cov.: 30 AF XY: 0.792 AC XY: 58862 AN XY: 74298

African (AFR) AF: 0.548 AC: 22686 AN: 41410

American (AMR) AF: 0.776 AC: 11835 AN: 15258

Ashkenazi Jewish (ASJ) AF: 0.889 AC: 3085 AN: 3470

East Asian (EAS) AF: 0.754 AC: 3875 AN: 5140

South Asian (SAS) AF: 0.845 AC: 4081 AN: 4832

European-Finnish (FIN) AF: 0.946 AC: 10006 AN: 10582

Middle Eastern (MID) AF: 0.901 AC: 265 AN: 294

European-Non Finnish (NFE) AF: 0.906 AC: 61561 AN: 67972

Other (OTH) AF: 0.824 AC: 1733 AN: 2104

Alfa AF: 0.866 Hom.: 197699

Bravo AF: 0.764

Asia WGS AF: 0.801 AC: 2786 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	0.52
DANN	Benign	0.41
PhyloP100		-1.0
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: rs4728533; hg19: chr7-75586536;