chr7-75985635-T-C

Variant names:

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

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_Moderate 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 (★★). 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
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: -6.08
• Publications: 27 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 Submitted by: ClinGen, 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 -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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001395413.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	POR	NM_001395413.1	MANE Select	c.1446T>C	p.Ala482Ala	synonymous	Exon 13 of 16	NP_001382342.1	P16435
	POR	NM_001382655.3		c.1500T>C	p.Ala500Ala	synonymous	Exon 14 of 17	NP_001369584.2
	POR	NM_001367562.3		c.1446T>C	p.Ala482Ala	synonymous	Exon 14 of 17	NP_001354491.2	P16435

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	POR	ENST00000461988.6	TSL:1 MANE Select	c.1446T>C	p.Ala482Ala	synonymous	Exon 13 of 16	ENSP00000419970.2	P16435
	POR	ENST00000447222.5	TSL:5	c.1605T>C	p.Ala535Ala	synonymous	Exon 12 of 15	ENSP00000393527.1	H0Y4R2
	POR	ENST00000910548.1		c.1446T>C	p.Ala482Ala	synonymous	Exon 13 of 16	ENSP00000580607.1

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

GnomAD2 exomes AF: 0.921 AC: 203905 AN: 221316 AF XY: 0.929

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

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

GnomAD4 genome AF: 0.872 AC: 132804 AN: 152298 Hom.: 59199 Cov.: 37 AF XY: 0.873 AC XY: 64987 AN XY: 74472

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

Alfa AF: 0.924 Hom.: 38699

Bravo AF: 0.855

Asia WGS AF: 0.873 AC: 3034 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	not specified (5)
-	-	2	Congenital adrenal hyperplasia due to cytochrome P450 oxidoreductase deficiency (2)
-	-	1	ADRENAL HYPERPLASIA, CONGENITAL, DUE TO 21-HYDROXYLASE DEFICIENCY (1)
-	-	1	Antley-Bixler syndrome with genital anomalies and disordered steroidogenesis (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	0.21
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)

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

Other links and lift over

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