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

Variant summary

Our verdict is Benign. Variant got -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. 14/20 in silico tools predict 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 Likely benign in UniProt.

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

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 made for transcript

Verdict is Benign. Variant got -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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
OPRM1	NM_000914.5 link	c.17C>T	p.Ala6Val	missense_variant	Exon 1 of 4	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.17C>T	p.Ala6Val	missense_variant	Exon 1 of 4	1	NM_000914.5	ENSP00000328264.7		P35372-1

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

GnomAD3 exomes

AF:

0.0169

AC:

4116

AN:

244044

Hom.:

370

AF XY:

0.0131

AC XY:

1732

AN XY:

132526

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 SAS exome

AF:

0.00297

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

Gnomad4 AFR exome

AF:

0.225

Gnomad4 AMR exome

AF:

0.0137

Gnomad4 ASJ exome

AF:

0.0128

Gnomad4 EAS exome

AF:

0.0000757

Gnomad4 SAS exome

AF:

0.00366

Gnomad4 FIN exome

AF:

0.0000376

Gnomad4 NFE exome

AF:

0.00130

Gnomad4 OTH exome

AF:

0.0178

GnomAD4 genome

AF:

0.0653

AC:

9944

AN:

152218

Hom.:

1058

Cov.:

AF XY:

0.0626

AC XY:

4663

AN XY:

74436

show subpopulations

Gnomad4 AFR

AF:

0.224

Gnomad4 AMR

AF:

0.0239

Gnomad4 ASJ

AF:

0.0112

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00435

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00190

Gnomad4 OTH

AF:

0.0469

Alfa

AF:

0.00685

Hom.:

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 v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.067

BayesDel_addAF

Benign

-0.72

BayesDel_noAF

Benign

-0.67

CADD

Benign

0.014

DANN

Benign

0.70

DEOGEN2

Benign

0.0037

.;.;T;T;.;.;.;.;.;.;.;.

Eigen

Benign

-1.3

Eigen_PC

Benign

-1.3

FATHMM_MKL

Benign

0.00013

LIST_S2

Benign

0.21

T;T;T;T;T;T;T;T;T;T;T;T

MetaRNN

Benign

0.0047

T;T;T;T;T;T;T;T;T;T;T;T

MetaSVM

Benign

-0.98

MutationAssessor

Benign

-0.34

.;.;.;N;N;N;N;N;N;N;N;N

PrimateAI

Benign

0.35

PROVEAN

Benign

0.14

N;N;.;N;N;N;N;N;N;N;N;N

REVEL

Benign

0.046

Sift

Benign

0.22

T;T;.;T;T;T;T;T;T;T;T;T

Sift4G

Benign

0.062

T;T;T;T;T;T;T;T;T;T;T;T

Polyphen

0.015, 0.0, 0.0010

.;B;.;B;B;B;B;B;B;B;B;B

Vest4

0.046, 0.018, 0.085, 0.086, 0.090, 0.089, 0.094, 0.095, 0.045, 0.099

MPC

0.049

ClinPred

0.0014

GERP RS

0.0079

Varity_R

0.019

gMVP

0.14

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

LitVar

Other links and lift over