rs9322446

Variant names:

• chr6-154087567-G-A
• rs9322446
• ENST00000522236:c.-248G>A

Variant summary

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

The NM_001145287.3(OPRM1):​c.-248G>A variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.149 in 984,764 control chromosomes in the GnomAD database, including 11,629 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 0.12 (1359 hom., cov: 32)
  • Exomes 𝑓: 0.15 (10270 hom.)
• Consequence: OPRM1 NM_001145287.3 5_prime_UTR
• Clinical Significance: drug response no assertion criteria provided O:1
• Conservation: PhyloP100: -0.357

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=-0.96).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.154 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
OPRM1	NM_000914.5	c.291-2259G>A		intron_variant	Intron 1 of 3	ENST00000330432.12	NP_000905.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
OPRM1	ENST00000330432.12	c.291-2259G>A		intron_variant	Intron 1 of 3	1	NM_000914.5	ENSP00000328264.7

Frequencies

GnomAD3 genomes AF: 0.120 AC: 18272 AN: 152054 Hom.: 1360 Cov.: 32

Gnomad AFR AF: 0.0600

Gnomad AMI AF: 0.0768

Gnomad AMR AF: 0.0928

Gnomad ASJ AF: 0.0784

Gnomad EAS AF: 0.0433

Gnomad SAS AF: 0.0586

Gnomad FIN AF: 0.249

Gnomad MID AF: 0.0981

Gnomad NFE AF: 0.156

Gnomad OTH AF: 0.113

GnomAD4 exome AF: 0.155 AC: 128781 AN: 832592 Hom.: 10270 Cov.: 31 AF XY: 0.154 AC XY: 59398 AN XY: 384510

Gnomad4 AFR exome AF: 0.0509

Gnomad4 AMR exome AF: 0.0752

Gnomad4 ASJ exome AF: 0.0831

Gnomad4 EAS exome AF: 0.0369

Gnomad4 SAS exome AF: 0.0651

Gnomad4 FIN exome AF: 0.216

Gnomad4 NFE exome AF: 0.161

Gnomad4 OTH exome AF: 0.129

GnomAD4 genome AF: 0.120 AC: 18267 AN: 152172 Hom.: 1359 Cov.: 32 AF XY: 0.121 AC XY: 9008 AN XY: 74382

Gnomad4 AFR AF: 0.0598

Gnomad4 AMR AF: 0.0925

Gnomad4 ASJ AF: 0.0784

Gnomad4 EAS AF: 0.0432

Gnomad4 SAS AF: 0.0587

Gnomad4 FIN AF: 0.249

Gnomad4 NFE AF: 0.156

Gnomad4 OTH AF: 0.111

Alfa AF: 0.132 Hom.: 349

Bravo AF: 0.109

Asia WGS AF: 0.0410 AC: 143 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	-0.96
CADD	Benign	0.46
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: rs9322446; hg19: chr6-154408702;