6-154090869-G-C

Variant names:

• chr6-154090869-G-C
• rs2075572
• NM_000914.5:c.644-83G>C

Variant summary

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

The NM_000914.5(OPRM1):​c.644-83G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.581 in 1,267,934 control chromosomes in the GnomAD database, including 217,224 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 0.55 (23380 hom., cov: 32)
  • Exomes 𝑓: 0.59 (193844 hom.)
• Consequence: OPRM1 NM_000914.5 intron
• Clinical Significance: drug response no assertion criteria provided O:1
• Conservation: PhyloP100: -0.929
• Publications: 52 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=-0.91).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.771 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
OPRM1	NM_000914.5	c.644-83G>C		intron_variant	Intron 2 of 3	ENST00000330432.12	NP_000905.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
OPRM1	ENST00000330432.12	c.644-83G>C		intron_variant	Intron 2 of 3	1	NM_000914.5	ENSP00000328264.7

Frequencies

GnomAD3 genomes AF: 0.548 AC: 83217 AN: 151954 Hom.: 23389 Cov.: 32

Gnomad AFR AF: 0.442

Gnomad AMI AF: 0.499

Gnomad AMR AF: 0.548

Gnomad ASJ AF: 0.596

Gnomad EAS AF: 0.791

Gnomad SAS AF: 0.748

Gnomad FIN AF: 0.610

Gnomad MID AF: 0.601

Gnomad NFE AF: 0.566

Gnomad OTH AF: 0.574

GnomAD4 exome AF: 0.585 AC: 653323 AN: 1115862 Hom.: 193844 AF XY: 0.589 AC XY: 328248 AN XY: 556928

African (AFR) AF: 0.439 AC: 11146 AN: 25366

American (AMR) AF: 0.532 AC: 15963 AN: 29980

Ashkenazi Jewish (ASJ) AF: 0.601 AC: 11305 AN: 18822

East Asian (EAS) AF: 0.782 AC: 29453 AN: 37660

South Asian (SAS) AF: 0.734 AC: 46472 AN: 63332

European-Finnish (FIN) AF: 0.608 AC: 29409 AN: 48358

Middle Eastern (MID) AF: 0.560 AC: 2570 AN: 4588

European-Non Finnish (NFE) AF: 0.570 AC: 478640 AN: 839708

Other (OTH) AF: 0.590 AC: 28365 AN: 48048

GnomAD4 genome AF: 0.547 AC: 83220 AN: 152072 Hom.: 23380 Cov.: 32 AF XY: 0.554 AC XY: 41208 AN XY: 74342

African (AFR) AF: 0.441 AC: 18311 AN: 41488

American (AMR) AF: 0.547 AC: 8346 AN: 15258

Ashkenazi Jewish (ASJ) AF: 0.596 AC: 2069 AN: 3472

East Asian (EAS) AF: 0.792 AC: 4107 AN: 5188

South Asian (SAS) AF: 0.748 AC: 3602 AN: 4818

European-Finnish (FIN) AF: 0.610 AC: 6452 AN: 10574

Middle Eastern (MID) AF: 0.599 AC: 176 AN: 294

European-Non Finnish (NFE) AF: 0.566 AC: 38495 AN: 67966

Other (OTH) AF: 0.574 AC: 1208 AN: 2104

Alfa AF: 0.426 Hom.: 1248

Bravo AF: 0.538

Asia WGS AF: 0.737 AC: 2562 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	-0.91
CADD	Benign	0.22
DANN	Benign	0.40
PhyloP100		-0.93
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs2075572; hg19: chr6-154412004; COSMIC: COSV57682973; COSMIC: COSV57682973;