chr7-75984764-C-G

Variant names:

• chr7-75984764-C-G
• rs4732516
• NM_001395413.1:c.1058-13C>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001395413.1(POR):​c.1058-13C>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.935 in 1,611,828 control chromosomes in the GnomAD database, including 710,378 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.85 (57007 hom., cov: 33)
  • Exomes 𝑓: 0.94 (653371 hom.)
• Consequence: POR NM_001395413.1 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: -2.76
• Publications: 15 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.97).
• BP6: Variant 7-75984764-C-G is Benign according to our data. Variant chr7-75984764-C-G is described in ClinVar as Benign. ClinVar VariationId is 138789.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.957 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
POR	NM_001395413.1	c.1058-13C>G		intron_variant	Intron 10 of 15	ENST00000461988.6	NP_001382342.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
POR	ENST00000461988.6	c.1058-13C>G		intron_variant	Intron 10 of 15	1	NM_001395413.1	ENSP00000419970.2

Frequencies

GnomAD3 genomes AF: 0.852 AC: 129552 AN: 152008 Hom.: 56976 Cov.: 33

Gnomad AFR AF: 0.610

Gnomad AMI AF: 0.923

Gnomad AMR AF: 0.871

Gnomad ASJ AF: 0.973

Gnomad EAS AF: 0.855

Gnomad SAS AF: 0.919

Gnomad FIN AF: 0.978

Gnomad MID AF: 0.934

Gnomad NFE AF: 0.963

Gnomad OTH AF: 0.878

GnomAD2 exomes AF: 0.911 AC: 225464 AN: 247390 AF XY: 0.921

Gnomad AFR exome AF: 0.602

Gnomad AMR exome AF: 0.840

Gnomad ASJ exome AF: 0.975

Gnomad EAS exome AF: 0.853

Gnomad FIN exome AF: 0.977

Gnomad NFE exome AF: 0.963

Gnomad OTH exome AF: 0.933

GnomAD4 exome AF: 0.944 AC: 1377896 AN: 1459702 Hom.: 653371 Cov.: 47 AF XY: 0.945 AC XY: 686189 AN XY: 726174

African (AFR) AF: 0.596 AC: 19907 AN: 33428

American (AMR) AF: 0.848 AC: 37916 AN: 44696

Ashkenazi Jewish (ASJ) AF: 0.974 AC: 25450 AN: 26116

East Asian (EAS) AF: 0.862 AC: 34210 AN: 39692

South Asian (SAS) AF: 0.920 AC: 79319 AN: 86244

European-Finnish (FIN) AF: 0.975 AC: 50794 AN: 52090

Middle Eastern (MID) AF: 0.943 AC: 5432 AN: 5762

European-Non Finnish (NFE) AF: 0.962 AC: 1069111 AN: 1111356

Other (OTH) AF: 0.924 AC: 55757 AN: 60318

GnomAD4 genome AF: 0.852 AC: 129635 AN: 152126 Hom.: 57007 Cov.: 33 AF XY: 0.854 AC XY: 63476 AN XY: 74364

African (AFR) AF: 0.610 AC: 25284 AN: 41458

American (AMR) AF: 0.871 AC: 13320 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.973 AC: 3377 AN: 3472

East Asian (EAS) AF: 0.855 AC: 4387 AN: 5128

South Asian (SAS) AF: 0.919 AC: 4442 AN: 4832

European-Finnish (FIN) AF: 0.978 AC: 10393 AN: 10624

Middle Eastern (MID) AF: 0.932 AC: 274 AN: 294

European-Non Finnish (NFE) AF: 0.963 AC: 65463 AN: 67998

Other (OTH) AF: 0.878 AC: 1853 AN: 2110

Alfa AF: 0.916 Hom.: 11938

Bravo AF: 0.832

Asia WGS AF: 0.859 AC: 2988 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:5

Feb 08, 2025

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 21, 2014

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

-

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

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

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Antley-Bixler syndrome with genital anomalies and disordered steroidogenesis Benign:1

Oct 25, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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

-

Pecori Giraldi Lab, University of Milan

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: case-control

This variant is intronic -

not provided Benign:1

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.97
CADD	Benign	0.22
DANN	Benign	0.38
PhyloP100		-2.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs4732516; hg19: chr7-75614082;