Genetic Variant OPRM1:p.Ala6Val (chr6-154039561-C-T) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_000914.5(OPRM1):c.17C>T(p.Ala6Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0133 in 1,612,066 control chromosomes in the GnomAD database, including 1,965 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.065 ( 1058 hom., cov: 32)

Exomes 𝑓: 0.0078 ( 907 hom. )

Consequence

OPRM1
NM_000914.5 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -1.92

Publications

83 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:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0046807826).

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.22 is higher than 0.05.

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	UniProt
OPRM1	NM_000914.5	MANE Select	c.17C>T	p.Ala6Val	missense	Exon 1 of 4	NP_000905.3	P35372-1
OPRM1	NM_001145279.4		c.296C>T	p.Ala99Val	missense	Exon 3 of 6	NP_001138751.1	P35372-10
OPRM1	NM_001285524.1		c.296C>T	p.Ala99Val	missense	Exon 2 of 5	NP_001272453.1	P35372-10

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
OPRM1	ENST00000330432.12	TSL:1 MANE Select	c.17C>T	p.Ala6Val	missense	Exon 1 of 4	ENSP00000328264.7	P35372-1
OPRM1	ENST00000434900.6	TSL:1	c.296C>T	p.Ala99Val	missense	Exon 3 of 6	ENSP00000394624.2	P35372-10
OPRM1	ENST00000360422.8	TSL:1	c.203C>T	p.Ala68Val	missense	Exon 1 of 4	ENSP00000353598.5	L0E130

Frequencies

GnomAD3 genomes

AF:

0.0651

AC:

9899

AN:

152100

Hom.:

1051

Cov.:

show subpopulations

Gnomad AFR

AF:

0.223

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0240

Gnomad ASJ

AF:

0.0112

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00435

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.0158

Gnomad NFE

AF:

0.00190

Gnomad OTH

AF:

0.0460

GnomAD2 exomes

AF:

0.0169

AC:

4116

AN:

244044

AF XY:

0.0131

show subpopulations

Gnomad AFR exome

AF:

0.222

Gnomad AMR exome

AF:

0.0104

Gnomad ASJ exome

AF:

0.0136

Gnomad EAS exome

AF:

0.000113

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00186

Gnomad OTH exome

AF:

0.0102

GnomAD4 exome

AF:

0.00784

AC:

11446

AN:

1459848

Hom.:

907

Cov.:

AF XY:

0.00700

AC XY:

5080

AN XY:

725962

show subpopulations

African (AFR)

AF:

0.225

AC:

7512

AN:

33458

American (AMR)

AF:

0.0137

AC:

607

AN:

44436

Ashkenazi Jewish (ASJ)

AF:

0.0128

AC:

333

AN:

26036

East Asian (EAS)

AF:

0.0000757

AC:

AN:

39622

South Asian (SAS)

AF:

0.00366

AC:

314

AN:

85772

European-Finnish (FIN)

AF:

0.0000376

AC:

AN:

53232

Middle Eastern (MID)

AF:

0.0267

AC:

154

AN:

5762

European-Non Finnish (NFE)

AF:

0.00130

AC:

1446

AN:

1111222

Other (OTH)

AF:

0.0178

AC:

1075

AN:

60308

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.467

Heterozygous variant carriers

624

1248

1873

2497

3121

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

244

488

732

976

1220

<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:

0.0653

AC:

9944

AN:

152218

Hom.:

1058

Cov.:

AF XY:

0.0626

AC XY:

4663

AN XY:

74436

show subpopulations

African (AFR)

AF:

0.224

AC:

9285

AN:

41490

American (AMR)

AF:

0.0239

AC:

366

AN:

15298

Ashkenazi Jewish (ASJ)

AF:

0.0112

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5188

South Asian (SAS)

AF:

0.00435

AC:

AN:

4824

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10622

Middle Eastern (MID)

AF:

0.0170

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00190

AC:

129

AN:

68010

Other (OTH)

AF:

0.0469

AC:

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.495

Heterozygous variant carriers

398

797

1195

1594

1992

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

188

282

376

470

<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:

0.0200

Hom.:

150

Bravo

AF:

0.0728

TwinsUK

AF:

0.000809

AC:

ALSPAC

AF:

0.00130

AC:

ESP6500AA

AF:

0.207

AC:

852

ESP6500EA

AF:

0.00202

AC:

ExAC

AF:

0.0207

AC:

2501

Asia WGS

AF:

0.0220

AC:

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.067

BayesDel_addAF

Benign

-0.72

BayesDel_noAF

Benign

-0.67

CADD

Benign

0.014

(source)

DANN

Benign

0.70

DEOGEN2

Benign

0.0037

Eigen

Benign

-1.3

Eigen_PC

Benign

-1.3

FATHMM_MKL

Benign

0.00013

LIST_S2

Benign

0.21

MetaRNN

Benign

0.0047

MetaSVM

Benign

-0.98

MutationAssessor

Benign

-0.34

PhyloP100

-1.9

PrimateAI

Benign

0.35

PROVEAN

Benign

0.14

REVEL

Benign

0.046

Sift

Benign

0.22

Sift4G

Benign

0.062

Polyphen

0.015

Vest4

0.046

MPC

0.049

ClinPred

0.0014

GERP RS

0.0079

PromoterAI

-0.025

Neutral

(source)

Varity_R

0.019

gMVP

0.14

Mutation Taster

=100/0

polymorphism (auto)

(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

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over