6-154010635-T-A

Variant summary

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

The ENST00000434900.6(OPRM1):c.-384T>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 0.0216 in 1,498,774 control chromosomes in the GnomAD database, including 1,057 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 0.026 (196 hom., cov: 32)
  • Exomes 𝑓: 0.021 (861 hom.)
• Consequence: OPRM1 ENST00000434900.6 5_prime_UTR
• Clinical Significance: drug response no assertion criteria provided O:1
• Conservation: PhyloP100: 1.16

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=-0.74).
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.126 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
OPRM1	NM_001145279.4	c.-384T>A		5_prime_UTR_variant	1/6
OPRM1	NM_001145280.4	c.-394T>A		5_prime_UTR_variant	1/4
OPRM1	NM_001145281.3	c.47+76T>A		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
OPRM1	ENST00000434900.6	c.-384T>A		5_prime_UTR_variant	1/6	1
OPRM1	ENST00000520282.5	c.-374T>A		5_prime_UTR_variant	1/3	1
OPRM1	ENST00000520708.5	c.-394T>A		5_prime_UTR_variant	1/4	1
OPRM1	ENST00000518759.5	c.47+76T>A		intron_variant		1

Frequencies

GnomAD3 genomes AF: 0.0262 AC: 3989 AN: 152042 Hom.: 187 Cov.: 32

Gnomad AFR AF: 0.00980

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.129

Gnomad ASJ AF: 0.0363

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.0176

Gnomad FIN AF: 0.0176

Gnomad MID AF: 0.0222

Gnomad NFE AF: 0.0165

Gnomad OTH AF: 0.0436

GnomAD4 exome AF: 0.0211 AC: 28428 AN: 1346614 Hom.: 861 Cov.: 30 AF XY: 0.0210 AC XY: 13793 AN XY: 656852

Gnomad4 AFR exome AF: 0.00936

Gnomad4 AMR exome AF: 0.188

Gnomad4 ASJ exome AF: 0.0305

Gnomad4 EAS exome AF: 0.000115

Gnomad4 SAS exome AF: 0.0277

Gnomad4 FIN exome AF: 0.0199

Gnomad4 NFE exome AF: 0.0166

Gnomad4 OTH exome AF: 0.0243

GnomAD4 genome AF: 0.0264 AC: 4012 AN: 152160 Hom.: 196 Cov.: 32 AF XY: 0.0273 AC XY: 2028 AN XY: 74404

Gnomad4 AFR AF: 0.00975

Gnomad4 AMR AF: 0.130

Gnomad4 ASJ AF: 0.0363

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.0176

Gnomad4 FIN AF: 0.0176

Gnomad4 NFE AF: 0.0165

Gnomad4 OTH AF: 0.0431

Alfa AF: 0.0217 Hom.: 17

Bravo AF: 0.0371

Asia WGS AF: 0.0180 AC: 62 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	-0.74
Cadd	Benign	7.3
Dann	Benign	0.78

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs115788842; hg19: chr6-154331770;