Genetic Variant OPRM1:p.Leu445Leu (chr6-154093438-C-T) – ACMG Classification: Benign (-13 pts)

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_StrongBP7BA1

The ENST00000229768.9(OPRM1):c.1333C>T(p.Leu445Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.676 in 1,612,816 control chromosomes in the GnomAD database, including 371,452 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as drug response (no stars).

Frequency

Genomes: 𝑓 0.67 ( 34184 hom., cov: 31)

Exomes 𝑓: 0.68 ( 337268 hom. )

Consequence

OPRM1
ENST00000229768.9 synonymous

Scores

Clinical Significance

drug response no assertion criteria provided O:1

Conservation

PhyloP100: 0.386

Publications

41 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: Benign. The variant received -13 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.79).

BP7

Synonymous conserved (PhyloP=0.386 with no splicing effect.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.876 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
OPRM1	NM_000914.5 link	c.1164+1966C>T		intron_variant	Intron 3 of 3	ENST00000330432.12	NP_000905.3	P35372-1G8XRH5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
OPRM1	ENST00000330432.12 link	c.1164+1966C>T		intron_variant	Intron 3 of 3	1	NM_000914.5	ENSP00000328264.7		P35372-1

Frequencies

GnomAD3 genomes

AF:

0.669

AC:

101319

AN:

151418

Hom.:

34180

Cov.:

show subpopulations

Gnomad AFR

AF:

0.624

Gnomad AMI

AF:

0.596

Gnomad AMR

AF:

0.730

Gnomad ASJ

AF:

0.688

Gnomad EAS

AF:

0.898

Gnomad SAS

AF:

0.833

Gnomad FIN

AF:

0.678

Gnomad MID

AF:

0.715

Gnomad NFE

AF:

0.652

Gnomad OTH

AF:

0.706

GnomAD2 exomes

AF:

0.713

AC:

177718

AN:

249284

AF XY:

0.716

show subpopulations

Gnomad AFR exome

AF:

0.629

Gnomad AMR exome

AF:

0.773

Gnomad ASJ exome

AF:

0.684

Gnomad EAS exome

AF:

0.884

Gnomad FIN exome

AF:

0.684

Gnomad NFE exome

AF:

0.657

Gnomad OTH exome

AF:

0.707

GnomAD4 exome

AF:

0.676

AC:

988529

AN:

1461280

Hom.:

337268

Cov.:

AF XY:

0.680

AC XY:

494529

AN XY:

726968

show subpopulations

African (AFR)

AF:

0.629

AC:

21065

AN:

33468

American (AMR)

AF:

0.770

AC:

34411

AN:

44704

Ashkenazi Jewish (ASJ)

AF:

0.686

AC:

17933

AN:

26132

East Asian (EAS)

AF:

0.891

AC:

35360

AN:

39686

South Asian (SAS)

AF:

0.820

AC:

70738

AN:

86226

European-Finnish (FIN)

AF:

0.683

AC:

36447

AN:

53384

Middle Eastern (MID)

AF:

0.670

AC:

3859

AN:

5760

European-Non Finnish (NFE)

AF:

0.654

AC:

727245

AN:

1111538

Other (OTH)

AF:

0.687

AC:

41471

AN:

60382

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.465

Heterozygous variant carriers

15726

31452

47178

62904

78630

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

19144

38288

57432

76576

95720

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.669

AC:

101357

AN:

151536

Hom.:

34184

Cov.:

AF XY:

0.676

AC XY:

50008

AN XY:

74006

show subpopulations

African (AFR)

AF:

0.623

AC:

25710

AN:

41260

American (AMR)

AF:

0.730

AC:

11127

AN:

15252

Ashkenazi Jewish (ASJ)

AF:

0.688

AC:

2383

AN:

3466

East Asian (EAS)

AF:

0.897

AC:

4611

AN:

5138

South Asian (SAS)

AF:

0.832

AC:

4000

AN:

4806

European-Finnish (FIN)

AF:

0.678

AC:

7109

AN:

10492

Middle Eastern (MID)

AF:

0.710

AC:

206

AN:

290

European-Non Finnish (NFE)

AF:

0.652

AC:

44185

AN:

67818

Other (OTH)

AF:

0.705

AC:

1487

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

1675

3351

5026

6702

8377

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

818

1636

2454

3272

4090

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.665

Hom.:

102497

Bravo

AF:

0.675

Asia WGS

AF:

0.844

AC:

2934

AN:

3478

EpiCase

AF:

0.662

EpiControl

AF:

0.668

ClinVar

Significance: drug response

Submissions summary: Other:1

Revision: no assertion criteria provided

LINK: link

Submissions by phenotype

Tramadol response

Other:1

Apr 28, 2018

Bruce Budowle Laboratory, University of North Texas Health Science Center

Significance:drug response

Review Status:no assertion criteria provided

Collection Method:research

- T:M1 = postmortem ratio or tramadol to O-desmethyltramadol; t-MP = model-based clustered metabolizer phenotype inferred from T:M1

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.79

CADD

Benign

(source)

DANN

Benign

0.62

PhyloP100

0.39

Mutation Taster

=100/0

polymorphism (auto)

(source)

Splicing

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

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over