rs9479757

Variant names:

• chr6-154090209-G-A
• rs9479757
• NM_000914.5:c.643+31G>A

Variant summary

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

The NM_000914.5(OPRM1):​c.643+31G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0892 in 1,468,760 control chromosomes in the GnomAD database, including 6,303 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 0.10 (874 hom., cov: 32)
  • Exomes 𝑓: 0.088 (5429 hom.)
• Consequence: OPRM1 NM_000914.5 intron
• Clinical Significance: drug response no assertion criteria provided O:1
• Conservation: PhyloP100: 1.48
• Publications: 36 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=-0.83).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.131 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
OPRM1	NM_000914.5	c.643+31G>A		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.643+31G>A		intron_variant	Intron 2 of 3	1	NM_000914.5	ENSP00000328264.7

Frequencies

GnomAD3 genomes AF: 0.102 AC: 15459 AN: 152030 Hom.: 869 Cov.: 32

Gnomad AFR AF: 0.134

Gnomad AMI AF: 0.128

Gnomad AMR AF: 0.0746

Gnomad ASJ AF: 0.113

Gnomad EAS AF: 0.0421

Gnomad SAS AF: 0.0255

Gnomad FIN AF: 0.124

Gnomad MID AF: 0.0601

Gnomad NFE AF: 0.0944

Gnomad OTH AF: 0.0925

GnomAD2 exomes AF: 0.0848 AC: 19104 AN: 225208 AF XY: 0.0817

Gnomad AFR exome AF: 0.133

Gnomad AMR exome AF: 0.0838

Gnomad ASJ exome AF: 0.115

Gnomad EAS exome AF: 0.0487

Gnomad FIN exome AF: 0.121

Gnomad NFE exome AF: 0.0910

Gnomad OTH exome AF: 0.0819

GnomAD4 exome AF: 0.0877 AC: 115481 AN: 1316612 Hom.: 5429 Cov.: 19 AF XY: 0.0856 AC XY: 56502 AN XY: 660018

African (AFR) AF: 0.133 AC: 4110 AN: 30872

American (AMR) AF: 0.0825 AC: 3602 AN: 43654

Ashkenazi Jewish (ASJ) AF: 0.111 AC: 2616 AN: 23584

East Asian (EAS) AF: 0.0404 AC: 1577 AN: 39060

South Asian (SAS) AF: 0.0250 AC: 1988 AN: 79470

European-Finnish (FIN) AF: 0.115 AC: 5510 AN: 47798

Middle Eastern (MID) AF: 0.0454 AC: 248 AN: 5464

European-Non Finnish (NFE) AF: 0.0920 AC: 91123 AN: 990970

Other (OTH) AF: 0.0844 AC: 4707 AN: 55740

GnomAD4 genome AF: 0.102 AC: 15493 AN: 152148 Hom.: 874 Cov.: 32 AF XY: 0.101 AC XY: 7542 AN XY: 74372

African (AFR) AF: 0.134 AC: 5560 AN: 41502

American (AMR) AF: 0.0745 AC: 1138 AN: 15270

Ashkenazi Jewish (ASJ) AF: 0.113 AC: 392 AN: 3470

East Asian (EAS) AF: 0.0424 AC: 220 AN: 5190

South Asian (SAS) AF: 0.0255 AC: 123 AN: 4822

European-Finnish (FIN) AF: 0.124 AC: 1313 AN: 10576

Middle Eastern (MID) AF: 0.0612 AC: 18 AN: 294

European-Non Finnish (NFE) AF: 0.0944 AC: 6419 AN: 68004

Other (OTH) AF: 0.0916 AC: 193 AN: 2108

Alfa AF: 0.0949 Hom.: 1254

Bravo AF: 0.0993

Asia WGS AF: 0.0350 AC: 120 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	-0.83
CADD	Benign	5.6
DANN	Benign	0.66
PhyloP100		1.5
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: rs9479757; hg19: chr6-154411344; COSMIC: COSV57686286; COSMIC: COSV57686286;