Genetic Variant OPRM1:p.Arg265Gly (chr6-154091101-C-G) – ACMG Classification: Uncertain_significance (3 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2PP3

The NM_000914.5(OPRM1):c.793C>G(p.Arg265Gly) 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. 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. R265H) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Consequence

OPRM1
NM_000914.5 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 7.91

Publications

15 publications found

Variant links:

Genes affected

OPRM1 (HGNC:8156): (opioid receptor mu 1) This gene encodes one of at least three opioid receptors in humans; the mu opioid receptor (MOR). The MOR is the principal target of endogenous opioid peptides and opioid analgesic agents such as beta-endorphin and enkephalins. The MOR also has an important role in dependence to other drugs of abuse, such as nicotine, cocaine, and alcohol via its modulation of the dopamine system. The NM_001008503.2:c.118A>G allele has been associated with opioid and alcohol addiction and variations in pain sensitivity but evidence for it having a causal role is conflicting. Multiple transcript variants encoding different isoforms have been found for this gene. Though the canonical MOR belongs to the superfamily of 7-transmembrane-spanning G-protein-coupled receptors some isoforms of this gene have only 6 transmembrane domains. [provided by RefSeq, Oct 2013]

OPRM1 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.827

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000914.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
OPRM1	NM_000914.5	MANE Select	c.793C>G	p.Arg265Gly	missense	Exon 3 of 4	NP_000905.3
OPRM1	NM_001145279.4		c.1072C>G	p.Arg358Gly	missense	Exon 5 of 6	NP_001138751.1
OPRM1	NM_001285524.1		c.1072C>G	p.Arg358Gly	missense	Exon 4 of 5	NP_001272453.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
OPRM1	ENST00000330432.12	TSL:1 MANE Select	c.793C>G	p.Arg265Gly	missense	Exon 3 of 4	ENSP00000328264.7
OPRM1	ENST00000434900.6	TSL:1	c.1072C>G	p.Arg358Gly	missense	Exon 5 of 6	ENSP00000394624.2
OPRM1	ENST00000360422.8	TSL:1	c.979C>G	p.Arg327Gly	missense	Exon 3 of 4	ENSP00000353598.5

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000756

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.92

BayesDel_addAF

Pathogenic

0.23

BayesDel_noAF

Uncertain

0.090

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.089

Eigen

Pathogenic

0.74

Eigen_PC

Pathogenic

0.77

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Pathogenic

1.0

M_CAP

Benign

0.062

MetaRNN

Pathogenic

0.83

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.3

PhyloP100

7.9

PrimateAI

Pathogenic

0.86

PROVEAN

Uncertain

-4.1

REVEL

Uncertain

0.43

Sift

Benign

0.32

Sift4G

Benign

0.13

Polyphen

1.0

Vest4

0.92

MutPred

0.54

Loss of MoRF binding (P = 0.0185)

MVP

0.66

MPC

0.37

ClinPred

0.99

GERP RS

6.0

Varity_R

0.61

gMVP

0.92

Mutation Taster

=16/84

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over