Genetic Variant OGFR:p.Phe273Leu (chr20-62812434-C-A) – ACMG Classification: Uncertain_significance (1 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2BP4

The NM_007346.4(OGFR):c.819C>A(p.Phe273Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000701 in 1,427,074 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 7.0e-7 ( 0 hom. )

Consequence

OGFR
NM_007346.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.826

Publications

0 publications found

Variant links:

Genes affected

OGFR (HGNC:15768): (opioid growth factor receptor) The protein encoded by this gene is a receptor for opioid growth factor (OGF), also known as [Met(5)]-enkephalin. OGF is a negative regulator of cell proliferation and tissue organization in a variety of processes. The encoded unbound receptor for OGF has been localized to the outer nuclear envelope, where it binds OGF and is translocated into the nucleus. The coding sequence of this gene contains a polymorphic region of 60 nt tandem imperfect repeat units. Several transcripts containing between zero and eight repeat units have been reported. [provided by RefSeq, Jul 2008]

OGFR links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.40565932).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
OGFR	NM_007346.4 link	c.819C>A	p.Phe273Leu	missense_variant	Exon 7 of 7	ENST00000290291.10	NP_031372.2	Q9NZT2-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
OGFR	ENST00000290291.10 link	c.819C>A	p.Phe273Leu	missense_variant	Exon 7 of 7	1	NM_007346.4	ENSP00000290291.6		Q9NZT2-1
OGFR	ENST00000370461.5 link	c.663C>A	p.Phe221Leu	missense_variant	Exon 5 of 5	2		ENSP00000359491.1		A0A0A0MRN5

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000494

AC:

AN:

202372

AF XY:

0.00

show subpopulations

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 FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000114

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

7.01e-7

AC:

AN:

1427074

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

706988

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

32500

American (AMR)

AF:

0.00

AC:

AN:

40102

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25158

East Asian (EAS)

AF:

0.00

AC:

AN:

37732

South Asian (SAS)

AF:

0.00

AC:

AN:

82068

European-Finnish (FIN)

AF:

0.00

AC:

AN:

50138

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5146

European-Non Finnish (NFE)

AF:

9.13e-7

AC:

AN:

1095388

Other (OTH)

AF:

0.00

AC:

AN:

58842

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.375

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.98

BayesDel_addAF

Benign

-0.052

BayesDel_noAF

Benign

-0.31

CADD

Benign

9.5

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.11

T;T;.

Eigen

Benign

-0.64

Eigen_PC

Benign

-0.83

FATHMM_MKL

Benign

0.49

LIST_S2

Benign

0.78

T;T;T

M_CAP

Benign

0.061

MetaRNN

Benign

0.41

T;T;T

MetaSVM

Benign

-0.52

MutationAssessor

Uncertain

2.2

M;.;.

PhyloP100

-0.83

PrimateAI

Pathogenic

0.79

PROVEAN

Pathogenic

-5.4

D;.;D

REVEL

Benign

0.23

Sift

Uncertain

0.026

D;.;D

Sift4G

Uncertain

0.058

T;T;D

Polyphen

0.83

P;.;.

Vest4

0.46

MutPred

0.79

Gain of catalytic residue at F273 (P = 0.0313);Gain of catalytic residue at F273 (P = 0.0313);.;

MVP

0.33

MPC

0.81

ClinPred

0.99

GERP RS

-5.0

Varity_R

0.33

gMVP

0.66

Mutation Taster

=68/32

polymorphism

(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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20-62812434-C-A

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over