NM_001395413.1:c.1446T>C

Variant names:

• chr7-75985635-T-C
• rs2228104
• NM_001395413.1:c.1446T>C

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

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
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: -6.08

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 -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 rank	MANE	Protein	UniProt
POR	NM_001395413.1	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	c.1446T>C	p.Ala482Ala	synonymous_variant	Exon 13 of 16	1	NM_001395413.1	ENSP00000419970.2

Frequencies

GnomAD3 genomes AF: 0.872 AC: 132709 AN: 152180 Hom.: 59158 Cov.: 37

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

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.: 71 AF XY: 0.951 AC XY: 679287 AN XY: 714326

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.: 37 AF XY: 0.873 AC XY: 64987 AN XY: 74472

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: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

- -

-

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

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. -

-

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

- -

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
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

Other links and lift over

dbSNP: rs2228104; hg19: chr7-75614953; COSMIC: COSV58694784; COSMIC: COSV58694784;