rs606545

Positions:

• chr6-154110430-G-A
• chr6-154110430-G-C

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The ENST00000452687.6(OPRM1):​c.*19G>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.222 in 1,457,050 control chromosomes in the GnomAD database, including 37,754 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 0.21 (3500 hom., cov: 30)
  • Exomes 𝑓: 0.22 (34254 hom.)
• Consequence: OPRM1 ENST00000452687.6 3_prime_UTR
• Clinical Significance: drug response no assertion criteria provided O:1
• Conservation: PhyloP100: 0.715

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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.248 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
OPRM1	NM_000914.5	c.1165-8253G>A		intron_variant		ENST00000330432.12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
OPRM1	ENST00000330432.12	c.1165-8253G>A		intron_variant		1	NM_000914.5	P1

Frequencies

GnomAD3 genomes AF: 0.207 AC: 31475 AN: 151876 Hom.: 3497 Cov.: 30

Gnomad AFR AF: 0.170

Gnomad AMI AF: 0.267

Gnomad AMR AF: 0.190

Gnomad ASJ AF: 0.197

Gnomad EAS AF: 0.0846

Gnomad SAS AF: 0.145

Gnomad FIN AF: 0.188

Gnomad MID AF: 0.225

Gnomad NFE AF: 0.251

Gnomad OTH AF: 0.190

GnomAD3 exomes AF: 0.195 AC: 29701 AN: 152462 Hom.: 3191 AF XY: 0.196 AC XY: 15859 AN XY: 80952

Gnomad AFR exome AF: 0.166

Gnomad AMR exome AF: 0.148

Gnomad ASJ exome AF: 0.203

Gnomad EAS exome AF: 0.0962

Gnomad SAS exome AF: 0.155

Gnomad FIN exome AF: 0.192

Gnomad NFE exome AF: 0.249

Gnomad OTH exome AF: 0.209

GnomAD4 exome AF: 0.224 AC: 292139 AN: 1305056 Hom.: 34254 Cov.: 21 AF XY: 0.223 AC XY: 144950 AN XY: 648652

Gnomad4 AFR exome AF: 0.156

Gnomad4 AMR exome AF: 0.151

Gnomad4 ASJ exome AF: 0.198

Gnomad4 EAS exome AF: 0.0858

Gnomad4 SAS exome AF: 0.156

Gnomad4 FIN exome AF: 0.198

Gnomad4 NFE exome AF: 0.241

Gnomad4 OTH exome AF: 0.215

GnomAD4 genome AF: 0.207 AC: 31508 AN: 151994 Hom.: 3500 Cov.: 30 AF XY: 0.202 AC XY: 14983 AN XY: 74270

Gnomad4 AFR AF: 0.170

Gnomad4 AMR AF: 0.190

Gnomad4 ASJ AF: 0.197

Gnomad4 EAS AF: 0.0846

Gnomad4 SAS AF: 0.146

Gnomad4 FIN AF: 0.188

Gnomad4 NFE AF: 0.251

Gnomad4 OTH AF: 0.192

Alfa AF: 0.231 Hom.: 820

Bravo AF: 0.204

Asia WGS AF: 0.122 AC: 426 AN: 3478

ClinVar

Significance: drug response

Submissions summary: Other:1

Revision: no assertion criteria provided

Submissions by phenotype

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
BayesDel_noAF	Benign	-0.90
CADD	Benign	7.7
DANN	Benign	0.39

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs606545; hg19: chr6-154431565; COSMIC: COSV57822672; COSMIC: COSV57822672;