rs1057868

chr7-75985688-C-T

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 2P and 20B. PM1 BP4_Strong BP6_Very_Strong BA1

The NM_001395413.1(POR):c.1499C>T(p.Ala500Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.291 in 1,591,240 control chromosomes in the GnomAD database, including 69,459 homozygotes. In-silico tool predicts a benign outcome for this variant. 11/16 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. A500A) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.27 (6048 hom., cov: 36)
  • Exomes 𝑓: 0.29 (63411 hom.)
• Consequence: POR NM_001395413.1 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 1.46

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 Benign. Variant got -18 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 8 uncertain in NM_001395413.1
• BP4: Computational evidence support a benign effect (MetaRNN=0.0018226206).
• BP6: Variant 7-75985688-C-T is Benign according to our data. Variant chr7-75985688-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 256840.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-75985688-C-T is described in Lovd as [Pathogenic]. Variant chr7-75985688-C-T is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.368 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
POR	NM_001395413.1	c.1499C>T	p.Ala500Val	missense_variant	13/16	ENST00000461988.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
POR	ENST00000461988.6	c.1499C>T	p.Ala500Val	missense_variant	13/16	1	NM_001395413.1	P4

Frequencies

GnomAD3 genomes AF: 0.273 AC: 41467 AN: 152154 Hom.: 6037 Cov.: 36

Gnomad AFR AF: 0.183

Gnomad AMI AF: 0.344

Gnomad AMR AF: 0.293

Gnomad ASJ AF: 0.257

Gnomad EAS AF: 0.382

Gnomad SAS AF: 0.358

Gnomad FIN AF: 0.414

Gnomad MID AF: 0.215

Gnomad NFE AF: 0.286

Gnomad OTH AF: 0.275

GnomAD3 exomes AF: 0.305 AC: 64499 AN: 211366 Hom.: 9927 AF XY: 0.309 AC XY: 35621 AN XY: 115164

Gnomad AFR exome AF: 0.184

Gnomad AMR exome AF: 0.282

Gnomad ASJ exome AF: 0.261

Gnomad EAS exome AF: 0.374

Gnomad SAS exome AF: 0.354

Gnomad FIN exome AF: 0.409

Gnomad NFE exome AF: 0.287

Gnomad OTH exome AF: 0.304

GnomAD4 exome AF: 0.293 AC: 421897 AN: 1438968 Hom.: 63411 Cov.: 86 AF XY: 0.296 AC XY: 210981 AN XY: 713612

Gnomad4 AFR exome AF: 0.176

Gnomad4 AMR exome AF: 0.284

Gnomad4 ASJ exome AF: 0.262

Gnomad4 EAS exome AF: 0.401

Gnomad4 SAS exome AF: 0.353

Gnomad4 FIN exome AF: 0.405

Gnomad4 NFE exome AF: 0.285

Gnomad4 OTH exome AF: 0.285

GnomAD4 genome AF: 0.273 AC: 41507 AN: 152272 Hom.: 6048 Cov.: 36 AF XY: 0.282 AC XY: 21029 AN XY: 74454

Gnomad4 AFR AF: 0.184

Gnomad4 AMR AF: 0.293

Gnomad4 ASJ AF: 0.257

Gnomad4 EAS AF: 0.382

Gnomad4 SAS AF: 0.357

Gnomad4 FIN AF: 0.414

Gnomad4 NFE AF: 0.286

Gnomad4 OTH AF: 0.276

Alfa AF: 0.286 Hom.: 5563

Bravo AF: 0.256

TwinsUK AF: 0.281 AC: 1043

ALSPAC AF: 0.279 AC: 1077

ESP6500AA AF: 0.168 AC: 698

ESP6500EA AF: 0.271 AC: 2247

ExAC AF: 0.276 AC: 32305

Asia WGS AF: 0.336 AC: 1170 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Dec 03, 2021	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

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

Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Mar 06, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	This variant is associated with the following publications: (PMID: 26227094, 26123203, 16467261, 18230729, 24113216, 19801957, 22547083, 20940534, 20697309, 18551037, 17635179, 20732302) -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 29, 2023	- -

Classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency Benign:1

Benign, criteria provided, single submitter

case-control

Pecori Giraldi Lab, University of Milan

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- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.49	T
BayesDel_noAF	Benign	-0.33
Cadd	Benign	15
Dann	Uncertain	0.98
Eigen	Benign	-0.86
Eigen_PC	Benign	-0.83
FATHMM_MKL	Benign	0.11	N
MetaRNN	Benign	0.0018	T;T;T
MetaSVM	Benign	-1.0	T
MutationTaster	Benign	1.0	P;P;P;P;P;P
PrimateAI	Benign	0.37	T
PROVEAN	Benign	-0.67	N;N;N
REVEL	Benign	0.13
Sift	Benign	0.22	T;T;T
Sift4G	Benign	0.29	T;T;T
Vest4		0.077
MPC		0.11
ClinPred		0.0031	T
GERP RS		3.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
gMVP		0.26

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: rs1057868; hg19: chr7-75615006; COSMIC: COSV58693460; COSMIC: COSV58693460;