rs623956

Positions:

• chr6-154108891-A-G
• chr6-154108891-A-T

Variant summary

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

The ENST00000414028.6(OPRM1):​c.*1096A>G variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.242 in 984,140 control chromosomes in the GnomAD database, including 29,520 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 (3484 hom., cov: 32)
  • Exomes 𝑓: 0.25 (26036 hom.)
• Consequence: OPRM1 ENST00000414028.6 3_prime_UTR
• Clinical Significance: drug response no assertion criteria provided O:1
• Conservation: PhyloP100: -0.184

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=-0.89).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.247 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
OPRM1	NM_000914.5	c.1165-9792A>G		intron_variant		ENST00000330432.12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
OPRM1	ENST00000330432.12	c.1165-9792A>G		intron_variant		1	NM_000914.5	P1

Frequencies

GnomAD3 genomes AF: 0.207 AC: 31407 AN: 152048 Hom.: 3481 Cov.: 32

Gnomad AFR AF: 0.168

Gnomad AMI AF: 0.269

Gnomad AMR AF: 0.189

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

GnomAD4 exome AF: 0.248 AC: 206463 AN: 831974 Hom.: 26036 Cov.: 23 AF XY: 0.248 AC XY: 95381 AN XY: 384268

Gnomad4 AFR exome AF: 0.157

Gnomad4 AMR exome AF: 0.169

Gnomad4 ASJ exome AF: 0.197

Gnomad4 EAS exome AF: 0.0958

Gnomad4 SAS exome AF: 0.150

Gnomad4 FIN exome AF: 0.225

Gnomad4 NFE exome AF: 0.254

Gnomad4 OTH exome AF: 0.230

GnomAD4 genome AF: 0.207 AC: 31440 AN: 152166 Hom.: 3484 Cov.: 32 AF XY: 0.201 AC XY: 14966 AN XY: 74402

Gnomad4 AFR AF: 0.168

Gnomad4 AMR AF: 0.189

Gnomad4 ASJ AF: 0.197

Gnomad4 EAS AF: 0.0847

Gnomad4 SAS AF: 0.146

Gnomad4 FIN AF: 0.188

Gnomad4 NFE AF: 0.251

Gnomad4 OTH AF: 0.192

Alfa AF: 0.233 Hom.: 545

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	-0.89
CADD	Benign	0.49
DANN	Benign	0.50

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs623956; hg19: chr6-154430026;