rs1799971

Positions:

• chr6-154039662-A-G

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 2P and 12B. PM1 BP4_Strong BA1

The NM_000914.5(OPRM1):​c.118A>G​(p.Asn40Asp) variant causes a missense change. The variant allele was found at a frequency of 0.151 in 1,613,692 control chromosomes in the GnomAD database, including 23,773 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance,drug response (no stars).

• Frequency:
  • Genomes: 𝑓 0.13 (1909 hom., cov: 32)
  • Exomes 𝑓: 0.15 (21864 hom.)
• Consequence: OPRM1 NM_000914.5 missense
• Clinical Significance: Uncertain significance; drug response no assertion criteria provided U:1 O:1
• Conservation: PhyloP100: 4.31

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]

ACMG classification

Verdict is Benign. Variant got -10 ACMG points.

• PM1: In a glycosylation_site N-linked (GlcNAc...) asparagine (size 0) in uniprot entity OPRM_HUMAN
• BP4: Computational evidence support a benign effect (MetaRNN=0.002016455).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.376 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
OPRM1	NM_000914.5	c.118A>G	p.Asn40Asp	missense_variant	1/4	ENST00000330432.12	NP_000905.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
OPRM1	ENST00000330432.12	c.118A>G	p.Asn40Asp	missense_variant	1/4	1	NM_000914.5	ENSP00000328264	P1

Frequencies

GnomAD3 genomes AF: 0.130 AC: 19734 AN: 152054 Hom.: 1912 Cov.: 32

Gnomad AFR AF: 0.0293

Gnomad AMI AF: 0.147

Gnomad AMR AF: 0.190

Gnomad ASJ AF: 0.176

Gnomad EAS AF: 0.391

Gnomad SAS AF: 0.380

Gnomad FIN AF: 0.199

Gnomad MID AF: 0.149

Gnomad NFE AF: 0.126

Gnomad OTH AF: 0.139

GnomAD3 exomes AF: 0.188 AC: 46959 AN: 249224 Hom.: 5913 AF XY: 0.196 AC XY: 26451 AN XY: 135238

Gnomad AFR exome AF: 0.0244

Gnomad AMR exome AF: 0.215

Gnomad ASJ exome AF: 0.187

Gnomad EAS exome AF: 0.372

Gnomad SAS exome AF: 0.363

Gnomad FIN exome AF: 0.198

Gnomad NFE exome AF: 0.125

Gnomad OTH exome AF: 0.180

GnomAD4 exome AF: 0.153 AC: 223836 AN: 1461520 Hom.: 21864 Cov.: 33 AF XY: 0.159 AC XY: 115536 AN XY: 726998

Gnomad4 AFR exome AF: 0.0231

Gnomad4 AMR exome AF: 0.205

Gnomad4 ASJ exome AF: 0.190

Gnomad4 EAS exome AF: 0.413

Gnomad4 SAS exome AF: 0.357

Gnomad4 FIN exome AF: 0.197

Gnomad4 NFE exome AF: 0.126

Gnomad4 OTH exome AF: 0.163

GnomAD4 genome AF: 0.130 AC: 19716 AN: 152172 Hom.: 1909 Cov.: 32 AF XY: 0.141 AC XY: 10499 AN XY: 74372

Gnomad4 AFR AF: 0.0292

Gnomad4 AMR AF: 0.190

Gnomad4 ASJ AF: 0.176

Gnomad4 EAS AF: 0.391

Gnomad4 SAS AF: 0.379

Gnomad4 FIN AF: 0.199

Gnomad4 NFE AF: 0.126

Gnomad4 OTH AF: 0.138

Alfa AF: 0.139 Hom.: 4404

Bravo AF: 0.120

TwinsUK AF: 0.129 AC: 479

ALSPAC AF: 0.127 AC: 489

ESP6500AA AF: 0.0306 AC: 122

ESP6500EA AF: 0.129 AC: 1070

ExAC AF: 0.185 AC: 22379

Asia WGS AF: 0.377 AC: 1311 AN: 3478

EpiCase AF: 0.132

EpiControl AF: 0.136

ClinVar

Significance: Uncertain significance; drug response

Submissions summary: Uncertain:1 Other:1

Revision: no assertion criteria provided

Submissions by phenotype

Opioid dependence, susceptibility to, 1 Uncertain:1

Uncertain significance, no assertion criteria provided

literature only

OMIM

Jun 30, 2009

- -

Tramadol response Other:1

drug response, no assertion criteria provided

research

Bruce Budowle Laboratory, University of North Texas Health Science Center

Apr 28, 2018

- 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
AlphaMissense	Benign	0.15
BayesDel_addAF	Benign	-0.57	T
BayesDel_noAF	Benign	-0.44
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.025	.;.;T;T;.;.;.;.;.;.;.;.
Eigen	Benign	-0.011
Eigen_PC	Benign	0.18
FATHMM_MKL	Benign	0.027	N
LIST_S2	Benign	0.69	T;T;T;T;T;T;T;T;T;T;T;T
MetaRNN	Benign	0.0020	T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	0.69	.;.;.;N;N;N;N;N;N;N;N;N
MutationTaster	Benign	0.0030	P;P;P;P;P;P;P;P;P;P;P;P;P
PrimateAI	Uncertain	0.62	T
PROVEAN	Benign	-2.1	N;N;.;N;N;N;N;N;N;N;N;N
REVEL	Benign	0.10
Sift	Uncertain	0.024	D;D;.;D;D;D;D;D;D;D;D;D
Sift4G	Uncertain	0.010	D;D;D;D;T;D;D;D;T;D;D;D
Polyphen		0.081, 0.23, 0.0070, 0.73, 0.49, 0.95, 0.0010, 0.22, 0.0030	.;B;.;B;B;P;P;P;B;P;B;B
Vest4		0.18, 0.097, 0.17, 0.18, 0.19, 0.19, 0.20, 0.22, 0.19, 0.19
MPC		0.11
ClinPred		0.028	T
GERP RS		5.8
Varity_R		0.17
gMVP		0.43

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

Other links and lift over

dbSNP: rs1799971; hg19: chr6-154360797; COSMIC: COSV57673061;