NM_001395413.1:c.180-6049A>G

Variant names:

• chr7-75966364-A-G
• rs7804806
• NM_001395413.1:c.180-6049A>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.180-6049A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.684 in 152,064 control chromosomes in the GnomAD database, including 35,754 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 0.68 (35754 hom., cov: 31)
• Consequence: POR NM_001395413.1 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.320
• 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=-0.93).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.727 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
POR	NM_001395413.1	c.180-6049A>G		intron_variant	Intron 2 of 15	ENST00000461988.6	NP_001382342.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
POR	ENST00000461988.6	c.180-6049A>G		intron_variant	Intron 2 of 15	1	NM_001395413.1	ENSP00000419970.2

Frequencies

GnomAD3 genomes AF: 0.684 AC: 103898 AN: 151946 Hom.: 35735 Cov.: 31

Gnomad AFR AF: 0.678

Gnomad AMI AF: 0.794

Gnomad AMR AF: 0.675

Gnomad ASJ AF: 0.574

Gnomad EAS AF: 0.576

Gnomad SAS AF: 0.749

Gnomad FIN AF: 0.768

Gnomad MID AF: 0.538

Gnomad NFE AF: 0.685

Gnomad OTH AF: 0.682

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

GnomAD4 genome AF: 0.684 AC: 103957 AN: 152064 Hom.: 35754 Cov.: 31 AF XY: 0.690 AC XY: 51259 AN XY: 74338

African (AFR) AF: 0.677 AC: 28097 AN: 41472

American (AMR) AF: 0.675 AC: 10322 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.574 AC: 1991 AN: 3468

East Asian (EAS) AF: 0.575 AC: 2957 AN: 5140

South Asian (SAS) AF: 0.747 AC: 3603 AN: 4822

European-Finnish (FIN) AF: 0.768 AC: 8143 AN: 10596

Middle Eastern (MID) AF: 0.544 AC: 160 AN: 294

European-Non Finnish (NFE) AF: 0.685 AC: 46531 AN: 67968

Other (OTH) AF: 0.677 AC: 1429 AN: 2110

Alfa AF: 0.673 Hom.: 42244

Bravo AF: 0.667

Asia WGS AF: 0.671 AC: 2333 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.93
CADD	Benign	3.7
DANN	Benign	0.41
PhyloP100		-0.32
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs7804806; hg19: chr7-75595682;