7-75985635-T-C

Position:

chr7-75985635-T-C

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_StrongBP6_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 (★★).

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:9

Conservation

PhyloP100: -6.08

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 links:

POR (HGNC:):

POR links:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.87).

BP6

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

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/exons	MANE	Protein	UniProt
POR	NM_001395413.1 linkuse as main transcript	c.1446T>C	p.Ala482Ala	synonymous_variant	13/16	ENST00000461988.6	NP_001382342.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
POR	ENST00000461988.6 linkuse as main transcript	c.1446T>C	p.Ala482Ala	synonymous_variant	13/16	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

GnomAD3 exomes

AF:

0.921

AC:

203905

AN:

221316

Hom.:

94668

AF XY:

0.929

AC XY:

112330

AN XY:

120888

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 SAS exome

AF:

0.932

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

Gnomad4 AFR exome

AF:

0.661

Gnomad4 AMR exome

AF:

0.868

Gnomad4 ASJ exome

AF:

0.975

Gnomad4 EAS exome

AF:

0.862

Gnomad4 SAS exome

AF:

0.930

Gnomad4 FIN exome

AF:

0.985

Gnomad4 NFE exome

AF:

0.965

Gnomad4 OTH exome

AF:

0.934

GnomAD4 genome

AF:

0.872

AC:

132804

AN:

152298

Hom.:

59199

Cov.:

AF XY:

0.873

AC XY:

64987

AN XY:

74472

show subpopulations

Gnomad4 AFR

AF:

0.666

Gnomad4 AMR

AF:

0.888

Gnomad4 ASJ

AF:

0.973

Gnomad4 EAS

AF:

0.859

Gnomad4 SAS

AF:

0.930

Gnomad4 FIN

AF:

0.987

Gnomad4 NFE

AF:

0.966

Gnomad4 OTH

AF:

0.898

Alfa

AF:

0.926

Hom.:

33898

Bravo

AF:

0.855

Asia WGS

AF:

0.873

AC:

3034

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:4

Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 21, 2014	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. -

Congenital adrenal hyperplasia due to cytochrome P450 oxidoreductase deficiency

Benign:2

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 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. -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -

Antley-Bixler syndrome with genital anomalies and disordered steroidogenesis

Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Oct 25, 2021

- -

Classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency

Benign:1

Benign, criteria provided, single submitter

case-control

Pecori Giraldi Lab, University of Milan

- -

not provided

Benign:1

Benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.87

CADD

Benign

0.21

DANN

Benign

0.58

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over