7-75985635-T-C

Variant names:

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_ModerateBP6_Very_StrongBP7BA1

The NM_001395413.1(POR):c.1446T>C(p.Ala482Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.943 in 1,592,914 control chromosomes in the GnomAD database, including 711,565 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. A482A) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.87 ( 59199 hom., cov: 37)

Exomes 𝑓: 0.95 ( 652366 hom. )

Consequence

POR
NM_001395413.1 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:10

Conservation

PhyloP100: -6.08

Publications

27 publications found

Variant links:

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

POR links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -19 ACMG points.

BP4

Computational evidence support a benign effect (REVEL=0.03).

BP6

Variant 7-75985635-T-C is Benign according to our data. Variant chr7-75985635-T-C is described in ClinVar as Benign. ClinVar VariationId is 138790.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-6.08 with no splicing effect.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.96 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
POR	NM_001395413.1 link	c.1446T>C	p.Ala482Ala	synonymous_variant	Exon 13 of 16	ENST00000461988.6	NP_001382342.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
POR	ENST00000461988.6 link	c.1446T>C	p.Ala482Ala	synonymous_variant	Exon 13 of 16	1	NM_001395413.1	ENSP00000419970.2		P16435

Frequencies

GnomAD3 genomes

AF:

0.872

AC:

132709

AN:

152180

Hom.:

59158

Cov.:

show subpopulations

Gnomad AFR

AF:

0.666

Gnomad AMI

AF:

0.923

Gnomad AMR

AF:

0.888

Gnomad ASJ

AF:

0.973

Gnomad EAS

AF:

0.859

Gnomad SAS

AF:

0.929

Gnomad FIN

AF:

0.987

Gnomad MID

AF:

0.943

Gnomad NFE

AF:

0.966

Gnomad OTH

AF:

0.898

GnomAD2 exomes

AF:

0.921

AC:

203905

AN:

221316

AF XY:

0.929

show subpopulations

Gnomad AFR exome

AF:

0.654

Gnomad AMR exome

AF:

0.861

Gnomad ASJ exome

AF:

0.976

Gnomad EAS exome

AF:

0.851

Gnomad FIN exome

AF:

0.987

Gnomad NFE exome

AF:

0.965

Gnomad OTH exome

AF:

0.943

GnomAD4 exome

AF:

0.950

AC:

1368698

AN:

1440616

Hom.:

652366

Cov.:

AF XY:

0.951

AC XY:

679287

AN XY:

714326

show subpopulations

African (AFR)

AF:

0.661

AC:

21868

AN:

33092

American (AMR)

AF:

0.868

AC:

36958

AN:

42568

Ashkenazi Jewish (ASJ)

AF:

0.975

AC:

24677

AN:

25308

East Asian (EAS)

AF:

0.862

AC:

33559

AN:

38910

South Asian (SAS)

AF:

0.930

AC:

77285

AN:

83070

European-Finnish (FIN)

AF:

0.985

AC:

49753

AN:

50512

Middle Eastern (MID)

AF:

0.956

AC:

5452

AN:

5702

European-Non Finnish (NFE)

AF:

0.965

AC:

1063542

AN:

1101932

Other (OTH)

AF:

0.934

AC:

55604

AN:

59522

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.478

Heterozygous variant carriers

3866

7733

11599

15466

19332

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

21506

43012

64518

86024

107530

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.872

AC:

132804

AN:

152298

Hom.:

59199

Cov.:

AF XY:

0.873

AC XY:

64987

AN XY:

74472

show subpopulations

African (AFR)

AF:

0.666

AC:

27683

AN:

41540

American (AMR)

AF:

0.888

AC:

13595

AN:

15308

Ashkenazi Jewish (ASJ)

AF:

0.973

AC:

3376

AN:

3470

East Asian (EAS)

AF:

0.859

AC:

4439

AN:

5168

South Asian (SAS)

AF:

0.930

AC:

4494

AN:

4832

European-Finnish (FIN)

AF:

0.987

AC:

10493

AN:

10628

Middle Eastern (MID)

AF:

0.942

AC:

277

AN:

294

European-Non Finnish (NFE)

AF:

0.966

AC:

65705

AN:

68030

Other (OTH)

AF:

0.898

AC:

1900

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.506

Heterozygous variant carriers

797

1594

2392

3189

3986

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

888

1776

2664

3552

4440

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.924

Hom.:

38699

Bravo

AF:

0.855

Asia WGS

AF:

0.873

AC:

3034

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:5

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

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

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

- -

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. -

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

- -

Congenital adrenal hyperplasia due to cytochrome P450 oxidoreductase deficiency

Benign:2

Jan 12, 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

- -

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

-0.87

CADD

Benign

0.21

(source)

DANN

Benign

0.58

PhyloP100

-6.1

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over