rs9479757

Positions:

• chr6-154090209-G-A

Variant summary

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

The NM_000914.5(OPRM1):​c.643+31G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0892 in 1,468,760 control chromosomes in the GnomAD database, including 6,303 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 0.10 (874 hom., cov: 32)
  • Exomes 𝑓: 0.088 (5429 hom.)
• Consequence: OPRM1 NM_000914.5 intron
• Clinical Significance: drug response no assertion criteria provided O:1
• Conservation: PhyloP100: 1.48

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=-0.83).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.131 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
OPRM1	NM_000914.5	c.643+31G>A		intron_variant		ENST00000330432.12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
OPRM1	ENST00000330432.12	c.643+31G>A		intron_variant		1	NM_000914.5	P1

Frequencies

GnomAD3 genomes AF: 0.102 AC: 15459 AN: 152030 Hom.: 869 Cov.: 32

Gnomad AFR AF: 0.134

Gnomad AMI AF: 0.128

Gnomad AMR AF: 0.0746

Gnomad ASJ AF: 0.113

Gnomad EAS AF: 0.0421

Gnomad SAS AF: 0.0255

Gnomad FIN AF: 0.124

Gnomad MID AF: 0.0601

Gnomad NFE AF: 0.0944

Gnomad OTH AF: 0.0925

GnomAD3 exomes AF: 0.0848 AC: 19104 AN: 225208 Hom.: 936 AF XY: 0.0817 AC XY: 9920 AN XY: 121394

Gnomad AFR exome AF: 0.133

Gnomad AMR exome AF: 0.0838

Gnomad ASJ exome AF: 0.115

Gnomad EAS exome AF: 0.0487

Gnomad SAS exome AF: 0.0257

Gnomad FIN exome AF: 0.121

Gnomad NFE exome AF: 0.0910

Gnomad OTH exome AF: 0.0819

GnomAD4 exome AF: 0.0877 AC: 115481 AN: 1316612 Hom.: 5429 Cov.: 19 AF XY: 0.0856 AC XY: 56502 AN XY: 660018

Gnomad4 AFR exome AF: 0.133

Gnomad4 AMR exome AF: 0.0825

Gnomad4 ASJ exome AF: 0.111

Gnomad4 EAS exome AF: 0.0404

Gnomad4 SAS exome AF: 0.0250

Gnomad4 FIN exome AF: 0.115

Gnomad4 NFE exome AF: 0.0920

Gnomad4 OTH exome AF: 0.0844

GnomAD4 genome AF: 0.102 AC: 15493 AN: 152148 Hom.: 874 Cov.: 32 AF XY: 0.101 AC XY: 7542 AN XY: 74372

Gnomad4 AFR AF: 0.134

Gnomad4 AMR AF: 0.0745

Gnomad4 ASJ AF: 0.113

Gnomad4 EAS AF: 0.0424

Gnomad4 SAS AF: 0.0255

Gnomad4 FIN AF: 0.124

Gnomad4 NFE AF: 0.0944

Gnomad4 OTH AF: 0.0916

Alfa AF: 0.0976 Hom.: 195

Bravo AF: 0.0993

Asia WGS AF: 0.0350 AC: 120 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	-0.83
CADD	Benign	5.6
DANN	Benign	0.66

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: rs9479757; hg19: chr6-154411344; COSMIC: COSV57686286; COSMIC: COSV57686286;