6-154107567-A-G

Variant names:

• chr6-154107567-A-G
• rs650245
• ENST00000419506.6:c.*4A>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The ENST00000419506.6(OPRM1):​c.*4A>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 0.905 in 718,432 control chromosomes in the GnomAD database, including 294,828 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 0.87 (58128 hom., cov: 32)
  • Exomes 𝑓: 0.91 (236700 hom.)
• Consequence: OPRM1 ENST00000419506.6 3_prime_UTR
• Clinical Significance: drug response no assertion criteria provided O:1
• Conservation: PhyloP100: -0.543
• Publications: 13 publications found

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

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-1.03).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.96 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
OPRM1	NM_000914.5	c.1165-11116A>G		intron_variant	Intron 3 of 3	ENST00000330432.12	NP_000905.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
OPRM1	ENST00000330432.12	c.1165-11116A>G		intron_variant	Intron 3 of 3	1	NM_000914.5	ENSP00000328264.7

Frequencies

GnomAD3 genomes AF: 0.872 AC: 132555 AN: 152084 Hom.: 58112 Cov.: 32

Gnomad AFR AF: 0.770

Gnomad AMI AF: 0.873

Gnomad AMR AF: 0.920

Gnomad ASJ AF: 0.886

Gnomad EAS AF: 0.983

Gnomad SAS AF: 0.974

Gnomad FIN AF: 0.877

Gnomad MID AF: 0.927

Gnomad NFE AF: 0.905

Gnomad OTH AF: 0.892

GnomAD2 exomes AF: 0.914 AC: 138482 AN: 151560 AF XY: 0.919

Gnomad AFR exome AF: 0.768

Gnomad AMR exome AF: 0.916

Gnomad ASJ exome AF: 0.887

Gnomad EAS exome AF: 0.980

Gnomad FIN exome AF: 0.880

Gnomad NFE exome AF: 0.909

Gnomad OTH exome AF: 0.920

GnomAD4 exome AF: 0.913 AC: 517207 AN: 566230 Hom.: 236700 Cov.: 0 AF XY: 0.918 AC XY: 280344 AN XY: 305464

African (AFR) AF: 0.775 AC: 12253 AN: 15812

American (AMR) AF: 0.915 AC: 31760 AN: 34720

Ashkenazi Jewish (ASJ) AF: 0.888 AC: 17789 AN: 20030

East Asian (EAS) AF: 0.978 AC: 31413 AN: 32108

South Asian (SAS) AF: 0.975 AC: 61205 AN: 62776

European-Finnish (FIN) AF: 0.885 AC: 43300 AN: 48948

Middle Eastern (MID) AF: 0.952 AC: 3882 AN: 4076

European-Non Finnish (NFE) AF: 0.907 AC: 287658 AN: 317060

Other (OTH) AF: 0.910 AC: 27947 AN: 30700

GnomAD4 genome AF: 0.871 AC: 132620 AN: 152202 Hom.: 58128 Cov.: 32 AF XY: 0.873 AC XY: 64938 AN XY: 74400

African (AFR) AF: 0.769 AC: 31912 AN: 41498

American (AMR) AF: 0.920 AC: 14079 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.886 AC: 3073 AN: 3470

East Asian (EAS) AF: 0.983 AC: 5093 AN: 5182

South Asian (SAS) AF: 0.974 AC: 4693 AN: 4820

European-Finnish (FIN) AF: 0.877 AC: 9280 AN: 10584

Middle Eastern (MID) AF: 0.925 AC: 272 AN: 294

European-Non Finnish (NFE) AF: 0.905 AC: 61537 AN: 68030

Other (OTH) AF: 0.893 AC: 1887 AN: 2112

Alfa AF: 0.893 Hom.: 125270

Bravo AF: 0.871

Asia WGS AF: 0.964 AC: 3355 AN: 3478

ClinVar

Significance: drug response

Submissions summary: Other:1

Revision: no assertion criteria provided

Submissions by phenotype

Tramadol response Other:1

Apr 28, 2018

Bruce Budowle Laboratory, University of North Texas Health Science Center

Significance: drug response

Review Status: no assertion criteria provided

Collection Method: research

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	-1.0
CADD	Benign	2.0
DANN	Benign	0.24
PhyloP100		-0.54
Mutation Taster		=100/0	polymorphism (auto)

Splicing

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

Other links and lift over

dbSNP: rs650245; hg19: chr6-154428702;