rs1135612

Variant names:

• chr7-75980359-A-G
• rs1135612
• NM_001395413.1:c.378A>G

Your query was ambiguous. Multiple possible variants found:

• chr7-75980359-A-G
• chr7-75980359-A-T

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.378A>G​(p.Pro126Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.254 in 1,612,602 control chromosomes in the GnomAD database, including 55,513 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.22 (4339 hom., cov: 32)
  • Exomes 𝑓: 0.26 (51174 hom.)
• Consequence: POR NM_001395413.1 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: -5.05
• Publications: 29 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=0.167).
• BP6: Variant 7-75980359-A-G is Benign according to our data. Variant chr7-75980359-A-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 256842.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-5.05 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.443 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.378A>G	p.Pro126Pro	synonymous	Exon 5 of 16	NP_001382342.1	P16435
	POR	NM_001382655.3		c.432A>G	p.Pro144Pro	synonymous	Exon 6 of 17	NP_001369584.2
	POR	NM_001367562.3		c.378A>G	p.Pro126Pro	synonymous	Exon 6 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.378A>G	p.Pro126Pro	synonymous	Exon 5 of 16	ENSP00000419970.2	P16435
	POR	ENST00000447222.5	TSL:5	c.303A>G	p.Pro101Pro	synonymous	Exon 4 of 15	ENSP00000393527.1	H0Y4R2
	POR	ENST00000910548.1		c.378A>G	p.Pro126Pro	synonymous	Exon 5 of 16	ENSP00000580607.1

Frequencies

GnomAD3 genomes AF: 0.216 AC: 32884 AN: 152028 Hom.: 4332 Cov.: 32

Gnomad AFR AF: 0.0776

Gnomad AMI AF: 0.168

Gnomad AMR AF: 0.319

Gnomad ASJ AF: 0.319

Gnomad EAS AF: 0.458

Gnomad SAS AF: 0.209

Gnomad FIN AF: 0.210

Gnomad MID AF: 0.357

Gnomad NFE AF: 0.255

Gnomad OTH AF: 0.234

GnomAD2 exomes AF: 0.276 AC: 68491 AN: 248368 AF XY: 0.269

Gnomad AFR exome AF: 0.0721

Gnomad AMR exome AF: 0.421

Gnomad ASJ exome AF: 0.313

Gnomad EAS exome AF: 0.470

Gnomad FIN exome AF: 0.212

Gnomad NFE exome AF: 0.256

Gnomad OTH exome AF: 0.271

GnomAD4 exome AF: 0.257 AC: 375938 AN: 1460456 Hom.: 51174 Cov.: 35 AF XY: 0.256 AC XY: 186175 AN XY: 726410

African (AFR) AF: 0.0706 AC: 2364 AN: 33474

American (AMR) AF: 0.405 AC: 18114 AN: 44692

Ashkenazi Jewish (ASJ) AF: 0.315 AC: 8234 AN: 26130

East Asian (EAS) AF: 0.457 AC: 18142 AN: 39682

South Asian (SAS) AF: 0.209 AC: 18067 AN: 86248

European-Finnish (FIN) AF: 0.209 AC: 11007 AN: 52544

Middle Eastern (MID) AF: 0.273 AC: 1571 AN: 5764

European-Non Finnish (NFE) AF: 0.254 AC: 282837 AN: 1111568

Other (OTH) AF: 0.259 AC: 15602 AN: 60354

GnomAD4 genome AF: 0.216 AC: 32906 AN: 152146 Hom.: 4339 Cov.: 32 AF XY: 0.216 AC XY: 16082 AN XY: 74378

African (AFR) AF: 0.0774 AC: 3216 AN: 41542

American (AMR) AF: 0.319 AC: 4876 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.319 AC: 1107 AN: 3468

East Asian (EAS) AF: 0.458 AC: 2351 AN: 5134

South Asian (SAS) AF: 0.210 AC: 1014 AN: 4822

European-Finnish (FIN) AF: 0.210 AC: 2223 AN: 10600

Middle Eastern (MID) AF: 0.366 AC: 107 AN: 292

European-Non Finnish (NFE) AF: 0.255 AC: 17353 AN: 67976

Other (OTH) AF: 0.239 AC: 506 AN: 2114

Alfa AF: 0.252 Hom.: 15929

Bravo AF: 0.225

Asia WGS AF: 0.322 AC: 1116 AN: 3478

EpiCase AF: 0.264

EpiControl AF: 0.254

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not specified (3)
-	-	2	Congenital adrenal hyperplasia due to cytochrome P450 oxidoreductase deficiency (2)
-	-	2	not provided (2)
-	-	1	ADRENAL HYPERPLASIA, CONGENITAL, DUE TO 21-HYDROXYLASE DEFICIENCY (1)
-	-	1	Antley-Bixler syndrome with genital anomalies and disordered steroidogenesis (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	0.040
DANN	Benign	0.37
PhyloP100		-5.1
Mutation Taster		=290/10	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: rs1135612; hg19: chr7-75609677; COSMIC: COSV67517774; COSMIC: COSV67517774;