6-154093240-A-C

Variant names:

• chr6-154093240-A-C
• rs9282821
• NM_000914.5:c.1164+1768A>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.1164+1768A>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.586 in 1,566,816 control chromosomes in the GnomAD database, including 272,523 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 (23725 hom., cov: 32)
  • Exomes 𝑓: 0.59 (248798 hom.)
• Consequence: OPRM1 NM_000914.5 intron
• Clinical Significance: drug response no assertion criteria provided O:1
• Conservation: PhyloP100: 0.0730
• Publications: 15 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=-0.81).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.772 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
OPRM1	NM_000914.5	c.1164+1768A>C		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.1164+1768A>C		intron_variant	Intron 3 of 3	1	NM_000914.5	ENSP00000328264.7

Frequencies

GnomAD3 genomes AF: 0.552 AC: 83821 AN: 151858 Hom.: 23735 Cov.: 32

Gnomad AFR AF: 0.443

Gnomad AMI AF: 0.497

Gnomad AMR AF: 0.552

Gnomad ASJ AF: 0.600

Gnomad EAS AF: 0.792

Gnomad SAS AF: 0.744

Gnomad FIN AF: 0.611

Gnomad MID AF: 0.598

Gnomad NFE AF: 0.574

Gnomad OTH AF: 0.581

GnomAD2 exomes AF: 0.606 AC: 140979 AN: 232546 AF XY: 0.615

Gnomad AFR exome AF: 0.447

Gnomad AMR exome AF: 0.552

Gnomad ASJ exome AF: 0.606

Gnomad EAS exome AF: 0.784

Gnomad FIN exome AF: 0.614

Gnomad NFE exome AF: 0.580

Gnomad OTH exome AF: 0.608

GnomAD4 exome AF: 0.590 AC: 834160 AN: 1414840 Hom.: 248798 Cov.: 26 AF XY: 0.594 AC XY: 415587 AN XY: 699630

African (AFR) AF: 0.441 AC: 14194 AN: 32176

American (AMR) AF: 0.547 AC: 22113 AN: 40424

Ashkenazi Jewish (ASJ) AF: 0.607 AC: 14988 AN: 24672

East Asian (EAS) AF: 0.781 AC: 30310 AN: 38810

South Asian (SAS) AF: 0.731 AC: 58925 AN: 80626

European-Finnish (FIN) AF: 0.611 AC: 32254 AN: 52824

Middle Eastern (MID) AF: 0.567 AC: 3172 AN: 5594

European-Non Finnish (NFE) AF: 0.577 AC: 623398 AN: 1081274

Other (OTH) AF: 0.596 AC: 34806 AN: 58440

GnomAD4 genome AF: 0.552 AC: 83822 AN: 151976 Hom.: 23725 Cov.: 32 AF XY: 0.558 AC XY: 41450 AN XY: 74272

African (AFR) AF: 0.443 AC: 18336 AN: 41422

American (AMR) AF: 0.551 AC: 8414 AN: 15266

Ashkenazi Jewish (ASJ) AF: 0.600 AC: 2078 AN: 3466

East Asian (EAS) AF: 0.792 AC: 4092 AN: 5168

South Asian (SAS) AF: 0.743 AC: 3582 AN: 4818

European-Finnish (FIN) AF: 0.611 AC: 6441 AN: 10550

Middle Eastern (MID) AF: 0.595 AC: 175 AN: 294

European-Non Finnish (NFE) AF: 0.574 AC: 39028 AN: 67974

Other (OTH) AF: 0.581 AC: 1224 AN: 2108

Alfa AF: 0.525 Hom.: 5219

Bravo AF: 0.543

Asia WGS AF: 0.734 AC: 2553 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	-0.81
CADD	Benign	4.6
DANN	Benign	0.76
PhyloP100		0.073
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: rs9282821; hg19: chr6-154414375; COSMIC: COSV57672957; COSMIC: COSV57672957;