7-75980485-C-G

Variant names:

• chr7-75980485-C-G
• rs372715546
• NM_001395413.1:c.504C>G

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_001395413.1(POR):​c.504C>G​(p.Phe168Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,460,696 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. F168F) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: POR NM_001395413.1 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:2
• Conservation: PhyloP100: 0.0220

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]

ACMG classification

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.955

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
POR	NM_001395413.1	c.504C>G	p.Phe168Leu	missense_variant	Exon 5 of 16	ENST00000461988.6	NP_001382342.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
POR	ENST00000461988.6	c.504C>G	p.Phe168Leu	missense_variant	Exon 5 of 16	1	NM_001395413.1	ENSP00000419970.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000402 AC: 1 AN: 248844 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 135144

Gnomad AFR exome AF: 0.0000647

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1460696 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 726622

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, single submitter

Submissions by phenotype

POR-related disorder Uncertain:1

Aug 13, 2024

PreventionGenetics, part of Exact Sciences

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

The POR c.513C>G variant is predicted to result in the amino acid substitution p.Phe171Leu. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.0065% of alleles in individuals of African descent in gnomAD. Although we suspect that this variant may be pathogenic, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Congenital adrenal hyperplasia due to cytochrome P450 oxidoreductase deficiency Uncertain:1

Sep 25, 2018

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces phenylalanine with leucine at codon 171 of the POR protein (p.Phe171Leu). The phenylalanine residue is moderately conserved and there is a small physicochemical difference between phenylalanine and leucine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with POR-related disease. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.060	T
BayesDel_noAF	Benign	-0.14
CADD	Benign	9.4
DANN	Benign	0.95
Eigen	Benign	-0.67
Eigen_PC	Benign	-0.92
FATHMM_MKL	Benign	0.60	D
M_CAP	Benign	0.054	D
MetaRNN	Pathogenic	0.95	D;D;D;D
MetaSVM	Benign	-0.99	T
PrimateAI	Uncertain	0.67	T
PROVEAN	Uncertain	-4.3	D;D;D;D
REVEL	Uncertain	0.55
Sift	Uncertain	0.0040	D;D;D;D
Sift4G	Uncertain	0.0070	D;D;D;D
Vest4		0.51, 0.51
MutPred		0.85		Loss of catalytic residue at F171 (P = 0.0085);Loss of catalytic residue at F171 (P = 0.0085);Loss of catalytic residue at F171 (P = 0.0085);Loss of catalytic residue at F171 (P = 0.0085);
MVP		0.87
MPC		0.52
ClinPred		0.93	D
GERP RS		-3.9
gMVP		0.75

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

Publications

LitVar

Other links and lift over

dbSNP: rs372715546; hg19: chr7-75609803;