6-154086832-C-T

Variant names:

• chr6-154086832-C-T
• rs563649
• ENST00000522236.1:c.-983C>T

Variant summary

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

The ENST00000522236.1(OPRM1):​c.-983C>T variant causes a 5 prime UTR premature start codon gain change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0911 in 984,998 control chromosomes in the GnomAD database, including 4,255 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 0.099 (827 hom., cov: 32)
  • Exomes 𝑓: 0.090 (3428 hom.)
• Consequence: OPRM1 ENST00000522236.1 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: drug response no assertion criteria provided O:1
• Conservation: PhyloP100: -1.01
• Publications: 65 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]

ENSG00000299884 (HGNC:):

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.98).
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.167 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
OPRM1	NM_000914.5	c.291-2994C>T		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.291-2994C>T		intron_variant	Intron 1 of 3	1	NM_000914.5	ENSP00000328264.7

Frequencies

GnomAD3 genomes AF: 0.0988 AC: 15018 AN: 152004 Hom.: 818 Cov.: 32

Gnomad AFR AF: 0.102

Gnomad AMI AF: 0.104

Gnomad AMR AF: 0.171

Gnomad ASJ AF: 0.0943

Gnomad EAS AF: 0.0952

Gnomad SAS AF: 0.0865

Gnomad FIN AF: 0.0652

Gnomad MID AF: 0.101

Gnomad NFE AF: 0.0868

Gnomad OTH AF: 0.112

GnomAD4 exome AF: 0.0896 AC: 74665 AN: 832876 Hom.: 3428 Cov.: 30 AF XY: 0.0898 AC XY: 34538 AN XY: 384620

African (AFR) AF: 0.109 AC: 1715 AN: 15776

American (AMR) AF: 0.237 AC: 233 AN: 984

Ashkenazi Jewish (ASJ) AF: 0.0852 AC: 439 AN: 5152

East Asian (EAS) AF: 0.103 AC: 375 AN: 3628

South Asian (SAS) AF: 0.0913 AC: 1502 AN: 16454

European-Finnish (FIN) AF: 0.0688 AC: 19 AN: 276

Middle Eastern (MID) AF: 0.0901 AC: 146 AN: 1620

European-Non Finnish (NFE) AF: 0.0888 AC: 67671 AN: 761694

Other (OTH) AF: 0.0940 AC: 2565 AN: 27292

GnomAD4 genome AF: 0.0989 AC: 15039 AN: 152122 Hom.: 827 Cov.: 32 AF XY: 0.0983 AC XY: 7307 AN XY: 74364

African (AFR) AF: 0.102 AC: 4229 AN: 41500

American (AMR) AF: 0.172 AC: 2629 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.0943 AC: 327 AN: 3466

East Asian (EAS) AF: 0.0946 AC: 490 AN: 5178

South Asian (SAS) AF: 0.0857 AC: 413 AN: 4818

European-Finnish (FIN) AF: 0.0652 AC: 689 AN: 10572

Middle Eastern (MID) AF: 0.0986 AC: 29 AN: 294

European-Non Finnish (NFE) AF: 0.0868 AC: 5902 AN: 67990

Other (OTH) AF: 0.112 AC: 236 AN: 2108

Alfa AF: 0.0924 Hom.: 2122

Bravo AF: 0.110

Asia WGS AF: 0.102 AC: 356 AN: 3476

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	-0.98
CADD	Benign	0.035
DANN	Benign	0.47
PhyloP100		-1.0
PromoterAI		-0.027	Neutral
Mutation Taster		=300/0	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: rs563649; hg19: chr6-154407967;