rs563649

chr6-154086832-C-T

Variant summary

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

The ENST00000522236.1(OPRM1):c.-983C>T variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0911 in 984,998 control chromosomes in the GnomAD database, including 4,255 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 0.099 (827 hom., cov: 32)
  • Exomes 𝑓: 0.090 (3428 hom.)
• Consequence: OPRM1 ENST00000522236.1 5_prime_UTR
• Clinical Significance: drug response no assertion criteria provided O:1
• Conservation: PhyloP100: -1.01

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=-0.98).
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.167 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
OPRM1	NM_000914.5	c.291-2994C>T		intron_variant		ENST00000330432.12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
OPRM1	ENST00000330432.12	c.291-2994C>T		intron_variant		1	NM_000914.5	P1

Frequencies

GnomAD3 genomes AF: 0.0988 AC: 15018 AN: 152004 Hom.: 818 Cov.: 32

Gnomad AFR AF: 0.102

Gnomad AMI AF: 0.104

Gnomad AMR AF: 0.171

Gnomad ASJ AF: 0.0943

Gnomad EAS AF: 0.0952

Gnomad SAS AF: 0.0865

Gnomad FIN AF: 0.0652

Gnomad MID AF: 0.101

Gnomad NFE AF: 0.0868

Gnomad OTH AF: 0.112

GnomAD4 exome AF: 0.0896 AC: 74665 AN: 832876 Hom.: 3428 Cov.: 30 AF XY: 0.0898 AC XY: 34538 AN XY: 384620

Gnomad4 AFR exome AF: 0.109

Gnomad4 AMR exome AF: 0.237

Gnomad4 ASJ exome AF: 0.0852

Gnomad4 EAS exome AF: 0.103

Gnomad4 SAS exome AF: 0.0913

Gnomad4 FIN exome AF: 0.0688

Gnomad4 NFE exome AF: 0.0888

Gnomad4 OTH exome AF: 0.0940

GnomAD4 genome AF: 0.0989 AC: 15039 AN: 152122 Hom.: 827 Cov.: 32 AF XY: 0.0983 AC XY: 7307 AN XY: 74364

Gnomad4 AFR AF: 0.102

Gnomad4 AMR AF: 0.172

Gnomad4 ASJ AF: 0.0943

Gnomad4 EAS AF: 0.0946

Gnomad4 SAS AF: 0.0857

Gnomad4 FIN AF: 0.0652

Gnomad4 NFE AF: 0.0868

Gnomad4 OTH AF: 0.112

Alfa AF: 0.0900 Hom.: 963

Bravo AF: 0.110

Asia WGS AF: 0.102 AC: 356 AN: 3476

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	-0.98
Cadd	Benign	0.035
Dann	Benign	0.47

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: rs563649; hg19: chr6-154407967;