chr7-75985179-G-T

Variant names:

Variant summary

Our verdict is Likely pathogenic. The variant received 9 ACMG points: 9P and 0B. PM2PM5PP3_StrongPP5

The NM_001395413.1(POR):c.1361G>T(p.Arg454Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 12/20 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R454H) has been classified as Likely pathogenic.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

POR
NM_001395413.1 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1U:1

Conservation

PhyloP100: 7.93

Publications

0 publications found

Variant links:

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, STRONG Submitted by: ClinGen, PanelApp Australia, 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

POR links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_pathogenic. The variant received 9 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr7-75985179-G-A is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 16907.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.958

PP5

Variant 7-75985179-G-T is Pathogenic according to our data. Variant chr7-75985179-G-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 3251474.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
POR	NM_001395413.1 link	c.1361G>T	p.Arg454Leu	missense_variant	Exon 12 of 16	ENST00000461988.6	NP_001382342.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
POR	ENST00000461988.6 link	c.1361G>T	p.Arg454Leu	missense_variant	Exon 12 of 16	1	NM_001395413.1	ENSP00000419970.2		P16435

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

1445240

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

719242

African (AFR)

AF:

0.00

AC:

AN:

33454

American (AMR)

AF:

0.00

AC:

AN:

44540

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26024

East Asian (EAS)

AF:

0.00

AC:

AN:

39642

South Asian (SAS)

AF:

0.00

AC:

AN:

86068

European-Finnish (FIN)

AF:

0.00

AC:

AN:

39268

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5762

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1110354

Other (OTH)

AF:

0.00

AC:

AN:

60128

GnomAD4 genome

Cov.:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1Uncertain:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Congenital adrenal hyperplasia due to cytochrome P450 oxidoreductase deficiency;C3150099:Antley-Bixler syndrome with genital anomalies and disordered steroidogenesis

Pathogenic:1

Apr 26, 2024

Fulgent Genetics, Fulgent Genetics

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not specified

Uncertain:1

Apr 08, 2024

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant summary: POR c.1361G>T (p.Arg454Leu) results in a non-conservative amino acid change in the encoded protein sequence. Three of three in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 232190 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.1361G>T has been reported in the literature in and individual affected with Congenital Adrenal Hyperplasia (Fan_2019). Additionally, another missense affecting the same codon (Arg454His) has been classified internally on the pathogenic spectrum. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication have been ascertained in the context of this evaluation (PMID: 31888681). No submitters have cited clinical-significance assessments for this variant to ClinVar. Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

1.0

BayesDel_addAF

Pathogenic

0.56

BayesDel_noAF

Pathogenic

0.57

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

Eigen

Pathogenic

0.94

Eigen_PC

Pathogenic

0.79

FATHMM_MKL

Uncertain

0.97

LIST_S2

Pathogenic

1.0

.;.;D

M_CAP

Pathogenic

0.63

MetaRNN

Pathogenic

0.96

D;D;D

MetaSVM

Pathogenic

1.1

PhyloP100

7.9

PrimateAI

Pathogenic

0.87

PROVEAN

Pathogenic

-6.9

D;D;D

REVEL

Pathogenic

0.97

Sift

Uncertain

0.0010

D;D;D

Sift4G

Pathogenic

0.0

D;D;D

Vest4

0.95

MVP

0.99

MPC

0.61

ClinPred

1.0

GERP RS

4.3

gMVP

0.89

Mutation Taster

=0/100

disease causing

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over