rs782200489

chr7-75983826-G-Achr7-75983826-G-Cchr7-75983826-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_001395413.1(POR):c.1027G>A(p.Asp343Asn) variant causes a missense change. The variant allele was found at a frequency of 0.000000685 in 1,458,898 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D343Y) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: POR NM_001395413.1 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 6.56

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
POR	NM_001395413.1	c.1027G>A	p.Asp343Asn	missense_variant	10/16	ENST00000461988.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
POR	ENST00000461988.6	c.1027G>A	p.Asp343Asn	missense_variant	10/16	1	NM_001395413.1	P4

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.00000408 AC: 1 AN: 244958 Hom.: 0 AF XY: 0.00000749 AC XY: 1 AN XY: 133576

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000330

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1458898 Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1 AN XY: 725648

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ExAC AF: 0.00000828 AC: 1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.068	T
BayesDel_noAF	Benign	-0.24
Cadd	Benign	22
Dann	Uncertain	1.0
Eigen	Benign	0.17
Eigen_PC	Benign	0.17
FATHMM_MKL	Uncertain	0.94	D
M_CAP	Uncertain	0.087	D
MetaRNN	Uncertain	0.65	D;D;D
MetaSVM	Benign	-0.58	T
MutationTaster	Benign	1.0	D;D;D;D;D;D
PrimateAI	Uncertain	0.56	T
PROVEAN	Pathogenic	-4.5	D;D;D
REVEL	Uncertain	0.51
Sift	Uncertain	0.0070	D;D;D
Sift4G	Uncertain	0.018	D;D;T
Vest4		0.46
MVP		0.83
MPC		0.12
ClinPred		0.92	D
GERP RS		4.3
gMVP		0.59

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: rs782200489; hg19: chr7-75613144;