chr7-75985688-C-T

Variant names:

• chr7-75985688-C-T
• rs1057868
• NM_001395413.1:c.1499C>T

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 2P and 20B. PM1 BP4_Strong BP6_Very_Strong BA1

The NM_001395413.1(POR):​c.1499C>T​(p.Ala500Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.291 in 1,591,240 control chromosomes in the GnomAD database, including 69,459 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. A500A) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.27 (6048 hom., cov: 36)
  • Exomes 𝑓: 0.29 (63411 hom.)
• Consequence: POR NM_001395413.1 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 1.46
• Publications: 207 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 -18 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 8 uncertain in NM_001395413.1
• BP4: Computational evidence support a benign effect (MetaRNN=0.0018226206).
• BP6: Variant 7-75985688-C-T is Benign according to our data. Variant chr7-75985688-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 256840.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.368 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.1499C>T	p.Ala500Val	missense	Exon 13 of 16	NP_001382342.1	P16435
	POR	NM_001382655.3		c.1553C>T	p.Ala518Val	missense	Exon 14 of 17	NP_001369584.2
	POR	NM_001367562.3		c.1499C>T	p.Ala500Val	missense	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.1499C>T	p.Ala500Val	missense	Exon 13 of 16	ENSP00000419970.2	P16435
	POR	ENST00000447222.5	TSL:5	c.1658C>T	p.Ala553Val	missense	Exon 12 of 15	ENSP00000393527.1	H0Y4R2
	POR	ENST00000910548.1		c.1499C>T	p.Ala500Val	missense	Exon 13 of 16	ENSP00000580607.1

Frequencies

GnomAD3 genomes AF: 0.273 AC: 41467 AN: 152154 Hom.: 6037 Cov.: 36

Gnomad AFR AF: 0.183

Gnomad AMI AF: 0.344

Gnomad AMR AF: 0.293

Gnomad ASJ AF: 0.257

Gnomad EAS AF: 0.382

Gnomad SAS AF: 0.358

Gnomad FIN AF: 0.414

Gnomad MID AF: 0.215

Gnomad NFE AF: 0.286

Gnomad OTH AF: 0.275

GnomAD2 exomes AF: 0.305 AC: 64499 AN: 211366 AF XY: 0.309

Gnomad AFR exome AF: 0.184

Gnomad AMR exome AF: 0.282

Gnomad ASJ exome AF: 0.261

Gnomad EAS exome AF: 0.374

Gnomad FIN exome AF: 0.409

Gnomad NFE exome AF: 0.287

Gnomad OTH exome AF: 0.304

GnomAD4 exome AF: 0.293 AC: 421897 AN: 1438968 Hom.: 63411 Cov.: 86 AF XY: 0.296 AC XY: 210981 AN XY: 713612

African (AFR) AF: 0.176 AC: 5843 AN: 33130

American (AMR) AF: 0.284 AC: 11822 AN: 41590

Ashkenazi Jewish (ASJ) AF: 0.262 AC: 6701 AN: 25598

East Asian (EAS) AF: 0.401 AC: 15493 AN: 38654

South Asian (SAS) AF: 0.353 AC: 29164 AN: 82638

European-Finnish (FIN) AF: 0.405 AC: 20269 AN: 50002

Middle Eastern (MID) AF: 0.291 AC: 1669 AN: 5726

European-Non Finnish (NFE) AF: 0.285 AC: 313960 AN: 1102086

Other (OTH) AF: 0.285 AC: 16976 AN: 59544

GnomAD4 genome AF: 0.273 AC: 41507 AN: 152272 Hom.: 6048 Cov.: 36 AF XY: 0.282 AC XY: 21029 AN XY: 74454

African (AFR) AF: 0.184 AC: 7635 AN: 41562

American (AMR) AF: 0.293 AC: 4487 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.257 AC: 892 AN: 3470

East Asian (EAS) AF: 0.382 AC: 1975 AN: 5172

South Asian (SAS) AF: 0.357 AC: 1723 AN: 4830

European-Finnish (FIN) AF: 0.414 AC: 4389 AN: 10606

Middle Eastern (MID) AF: 0.224 AC: 66 AN: 294

European-Non Finnish (NFE) AF: 0.286 AC: 19443 AN: 68010

Other (OTH) AF: 0.276 AC: 583 AN: 2112

Alfa AF: 0.285 Hom.: 15285

Bravo AF: 0.256

TwinsUK AF: 0.281 AC: 1043

ALSPAC AF: 0.279 AC: 1077

ESP6500AA AF: 0.168 AC: 698

ESP6500EA AF: 0.271 AC: 2247

ExAC AF: 0.276 AC: 32305

Asia WGS AF: 0.336 AC: 1170 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	2	Congenital adrenal hyperplasia due to cytochrome P450 oxidoreductase deficiency (2)
-	-	2	not specified (2)
-	-	1	ADRENAL HYPERPLASIA, CONGENITAL, DUE TO 21-HYDROXYLASE DEFICIENCY (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.069
BayesDel_addAF	Benign	-0.49	T
BayesDel_noAF	Benign	-0.33
CADD	Benign	15
DANN	Uncertain	0.98
Eigen	Benign	-0.86
Eigen_PC	Benign	-0.83
FATHMM_MKL	Benign	0.11	N
LIST_S2	Benign	0.67	T
MetaRNN	Benign	0.0018	T
MetaSVM	Benign	-1.0	T
PhyloP100		1.5
PrimateAI	Benign	0.37	T
PROVEAN	Benign	-0.67	N
REVEL	Benign	0.13
Sift	Benign	0.22	T
Sift4G	Benign	0.29	T
Vest4		0.077
MPC		0.11
ClinPred		0.0031	T
GERP RS		3.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
gMVP		0.26
Mutation Taster		=95/5	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: rs1057868; hg19: chr7-75615006; COSMIC: COSV58693460; COSMIC: COSV58693460;