rs10239977

Variant names:

• chr7-75979668-C-T
• rs10239977
• NM_001395413.1:c.357+89C>T

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.357+89C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.319 in 1,540,602 control chromosomes in the GnomAD database, including 83,573 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.27 (6166 hom., cov: 33)
  • Exomes 𝑓: 0.33 (77407 hom.)
• Consequence: POR NM_001395413.1 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -2.87
• Publications: 11 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.92).
• BP6: Variant 7-75979668-C-T is Benign according to our data. Variant chr7-75979668-C-T is described in ClinVar as Benign. ClinVar VariationId is 1274770.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.352 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.357+89C>T		intron	N/A	NP_001382342.1	P16435
	POR	NM_001382655.3		c.411+89C>T		intron	N/A	NP_001369584.2
	POR	NM_001367562.3		c.357+89C>T		intron	N/A	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.357+89C>T		intron	N/A	ENSP00000419970.2	P16435
	POR	ENST00000447222.5	TSL:5	c.282+89C>T		intron	N/A	ENSP00000393527.1	H0Y4R2
	POR	ENST00000910548.1		c.357+89C>T		intron	N/A	ENSP00000580607.1

Frequencies

GnomAD3 genomes AF: 0.265 AC: 40310 AN: 151950 Hom.: 6172 Cov.: 33

Gnomad AFR AF: 0.134

Gnomad AMI AF: 0.396

Gnomad AMR AF: 0.256

Gnomad ASJ AF: 0.245

Gnomad EAS AF: 0.0330

Gnomad SAS AF: 0.260

Gnomad FIN AF: 0.321

Gnomad MID AF: 0.253

Gnomad NFE AF: 0.355

Gnomad OTH AF: 0.284

GnomAD4 exome AF: 0.325 AC: 451759 AN: 1388534 Hom.: 77407 Cov.: 22 AF XY: 0.324 AC XY: 222112 AN XY: 686380

African (AFR) AF: 0.125 AC: 4049 AN: 32286

American (AMR) AF: 0.188 AC: 7849 AN: 41802

Ashkenazi Jewish (ASJ) AF: 0.249 AC: 5850 AN: 23522

East Asian (EAS) AF: 0.0351 AC: 1356 AN: 38618

South Asian (SAS) AF: 0.259 AC: 20961 AN: 80846

European-Finnish (FIN) AF: 0.330 AC: 12900 AN: 39114

Middle Eastern (MID) AF: 0.268 AC: 1461 AN: 5442

European-Non Finnish (NFE) AF: 0.355 AC: 380107 AN: 1069384

Other (OTH) AF: 0.299 AC: 17226 AN: 57520

GnomAD4 genome AF: 0.265 AC: 40300 AN: 152068 Hom.: 6166 Cov.: 33 AF XY: 0.261 AC XY: 19430 AN XY: 74346

African (AFR) AF: 0.134 AC: 5562 AN: 41482

American (AMR) AF: 0.256 AC: 3909 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.245 AC: 848 AN: 3468

East Asian (EAS) AF: 0.0327 AC: 169 AN: 5170

South Asian (SAS) AF: 0.260 AC: 1251 AN: 4820

European-Finnish (FIN) AF: 0.321 AC: 3401 AN: 10588

Middle Eastern (MID) AF: 0.235 AC: 69 AN: 294

European-Non Finnish (NFE) AF: 0.355 AC: 24141 AN: 67950

Other (OTH) AF: 0.279 AC: 590 AN: 2112

Alfa AF: 0.306 Hom.: 13165

Bravo AF: 0.250

Asia WGS AF: 0.148 AC: 515 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	0.56
DANN	Benign	0.79
PhyloP100		-2.9
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)		0.0		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: rs10239977; hg19: chr7-75608986; COSMIC: COSV67517099; COSMIC: COSV67517099;