7-75985594-G-C

Position:

• chr7-75985594-G-C

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_Strong BS1_Supporting BS2

The NM_001395413.1(POR):​c.1405G>C​(p.Val469Leu) variant causes a missense change. The variant allele was found at a frequency of 0.000271 in 1,562,518 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. 11/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00030 (0 hom., cov: 36)
  • Exomes 𝑓: 0.00027 (3 hom.)
• Consequence: POR NM_001395413.1 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4 B:2
• Conservation: PhyloP100: 5.04

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 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -9 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.029947221).
• BS1: Variant frequency is greater than expected in population mid. gnomad4_exome allele frequency = 0.000268 (378/1410156) while in subpopulation MID AF= 0.00815 (45/5524). AF 95% confidence interval is 0.00626. There are 3 homozygotes in gnomad4_exome. There are 218 alleles in male gnomad4_exome subpopulation. Median coverage is 65. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High Homozygotes in GnomAdExome4 at 3 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
POR	NM_001395413.1	c.1405G>C	p.Val469Leu	missense_variant	13/16	ENST00000461988.6	NP_001382342.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
POR	ENST00000461988.6	c.1405G>C	p.Val469Leu	missense_variant	13/16	1	NM_001395413.1	ENSP00000419970.2

Frequencies

GnomAD3 genomes AF: 0.000296 AC: 45 AN: 152244 Hom.: 0 Cov.: 36

Gnomad AFR AF: 0.000121

Gnomad AMI AF: 0.00329

Gnomad AMR AF: 0.00131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00124

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000147

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.000447 AC: 90 AN: 201346 Hom.: 0 AF XY: 0.000561 AC XY: 61 AN XY: 108730

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000740

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00180

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000237

Gnomad OTH exome AF: 0.00119

GnomAD4 exome AF: 0.000268 AC: 378 AN: 1410156 Hom.: 3 Cov.: 65 AF XY: 0.000314 AC XY: 218 AN XY: 694058

Gnomad4 AFR exome AF: 0.0000305

Gnomad4 AMR exome AF: 0.000651

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00183

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000127

Gnomad4 OTH exome AF: 0.000429

GnomAD4 genome AF: 0.000295 AC: 45 AN: 152362 Hom.: 0 Cov.: 36 AF XY: 0.000309 AC XY: 23 AN XY: 74502

Gnomad4 AFR AF: 0.000120

Gnomad4 AMR AF: 0.00131

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00124

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000147

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.0000346 Hom.: 0

Bravo AF: 0.000502

ExAC AF: 0.000495 AC: 59

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:4 Benign:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Congenital adrenal hyperplasia due to cytochrome P450 oxidoreductase deficiency Uncertain:2 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -
Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 27, 2024	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Baylor Genetics	Jul 31, 2019	This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868]. -

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Mendelics

May 04, 2022

- -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Oct 24, 2019

The POR c.1414G>C; p.Val472Leu variant (rs72557946), to our knowledge, has not been reported in the medical literature or gene specific databases. This variant is found in the general population with an allele frequency in South Asian populations of 0.18% (40/22,222 alleles) in the Genome Aggregation Database. The valine at codon 472 is moderately conserved (Alamut v.2.11) and computational analyses (SIFT, PolyPhen-2) predict that this variant is tolerated. However, based on the available information, the clinical significance of this variant is uncertain. -

POR-related disorder Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

May 19, 2024

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.38	T
BayesDel_noAF	Benign	-0.34
CADD	Benign	22
DANN	Benign	0.97
Eigen	Benign	-0.14
Eigen_PC	Benign	-0.072
FATHMM_MKL	Uncertain	0.87	D
LIST_S2	Benign	0.85	.;.;T
M_CAP	Uncertain	0.15	D
MetaRNN	Benign	0.030	T;T;T
MetaSVM	Benign	-0.60	T
PrimateAI	Uncertain	0.76	T
PROVEAN	Benign	-1.8	N;N;N
REVEL	Benign	0.19
Sift	Benign	0.075	T;T;D
Sift4G	Benign	0.080	T;T;T
Vest4		0.52
MVP		0.83
MPC		0.13
ClinPred		0.045	T
GERP RS		3.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
gMVP		0.35

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: rs72557946; hg19: chr7-75614912;