rs17685

Positions:

• chr7-75986787-G-A
• chr7-75986787-G-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001395413.1(POR):​c.*306G>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.28 in 574,552 control chromosomes in the GnomAD database, including 23,649 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.26 (5398 hom., cov: 34)
  • Exomes 𝑓: 0.29 (18251 hom.)
• Consequence: POR NM_001395413.1 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -4.47

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]

TMEM120A (HGNC:21697): (transmembrane protein 120A) Predicted to enable ion channel activity. Involved in fat cell differentiation; protein heterooligomerization; and protein homooligomerization. Predicted to be located in plasma membrane. Predicted to be active in membrane. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.66).
• BP6: Variant 7-75986787-G-A is Benign according to our data. Variant chr7-75986787-G-A is described in ClinVar as [Benign]. Clinvar id is 360731.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.345 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
POR	NM_001395413.1	c.*306G>A		3_prime_UTR_variant	16/16	ENST00000461988.6
TMEM120A	NM_031925.3			downstream_gene_variant		ENST00000493111.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
POR	ENST00000461988.6	c.*306G>A		3_prime_UTR_variant	16/16	1	NM_001395413.1	P4
TMEM120A	ENST00000493111.7			downstream_gene_variant		1	NM_031925.3	P1

Frequencies

GnomAD3 genomes AF: 0.258 AC: 39287 AN: 152006 Hom.: 5388 Cov.: 34

Gnomad AFR AF: 0.180

Gnomad AMI AF: 0.344

Gnomad AMR AF: 0.224

Gnomad ASJ AF: 0.233

Gnomad EAS AF: 0.358

Gnomad SAS AF: 0.347

Gnomad FIN AF: 0.399

Gnomad MID AF: 0.212

Gnomad NFE AF: 0.278

Gnomad OTH AF: 0.259

GnomAD4 exome AF: 0.288 AC: 121518 AN: 422428 Hom.: 18251 Cov.: 0 AF XY: 0.291 AC XY: 64066 AN XY: 220346

Gnomad4 AFR exome AF: 0.179

Gnomad4 AMR exome AF: 0.217

Gnomad4 ASJ exome AF: 0.241

Gnomad4 EAS exome AF: 0.361

Gnomad4 SAS exome AF: 0.334

Gnomad4 FIN exome AF: 0.387

Gnomad4 NFE exome AF: 0.274

Gnomad4 OTH exome AF: 0.276

GnomAD4 genome AF: 0.259 AC: 39327 AN: 152124 Hom.: 5398 Cov.: 34 AF XY: 0.266 AC XY: 19788 AN XY: 74374

Gnomad4 AFR AF: 0.181

Gnomad4 AMR AF: 0.224

Gnomad4 ASJ AF: 0.233

Gnomad4 EAS AF: 0.358

Gnomad4 SAS AF: 0.346

Gnomad4 FIN AF: 0.399

Gnomad4 NFE AF: 0.278

Gnomad4 OTH AF: 0.260

Alfa AF: 0.265 Hom.: 7499

Bravo AF: 0.239

Asia WGS AF: 0.318 AC: 1105 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 26, 2018	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Congenital adrenal hyperplasia due to cytochrome P450 oxidoreductase deficiency Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 2018

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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.66
CADD	Benign	0.039
DANN	Benign	0.86
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

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: rs17685; hg19: chr7-75616105;