6-154093311-A-T

Variant names:

• chr6-154093311-A-T
• rs540825
• ENST00000229768.9:c.1206A>T

Variant summary

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

The ENST00000229768.9(OPRM1):​c.1206A>T​(p.Gln402His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.773 in 1,612,926 control chromosomes in the GnomAD database, including 485,112 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/17 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as drug response (no stars).

• Frequency:
  • Genomes: 𝑓 0.82 (51993 hom., cov: 32)
  • Exomes 𝑓: 0.77 (433119 hom.)
• Consequence: OPRM1 ENST00000229768.9 missense
• Clinical Significance: drug response no assertion criteria provided O:1
• Conservation: PhyloP100: -0.683
• Publications: 53 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 (MetaRNN=1.5697856E-6).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.927 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
OPRM1	NM_000914.5	c.1164+1839A>T		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+1839A>T		intron_variant	Intron 3 of 3	1	NM_000914.5	ENSP00000328264.7

Frequencies

GnomAD3 genomes AF: 0.822 AC: 124996 AN: 152066 Hom.: 51942 Cov.: 32

Gnomad AFR AF: 0.935

Gnomad AMI AF: 0.728

Gnomad AMR AF: 0.823

Gnomad ASJ AF: 0.789

Gnomad EAS AF: 0.940

Gnomad SAS AF: 0.860

Gnomad FIN AF: 0.804

Gnomad MID AF: 0.775

Gnomad NFE AF: 0.747

Gnomad OTH AF: 0.833

GnomAD2 exomes AF: 0.809 AC: 201769 AN: 249428 AF XY: 0.805

Gnomad AFR exome AF: 0.937

Gnomad AMR exome AF: 0.865

Gnomad ASJ exome AF: 0.785

Gnomad EAS exome AF: 0.933

Gnomad FIN exome AF: 0.803

Gnomad NFE exome AF: 0.748

Gnomad OTH exome AF: 0.794

GnomAD4 exome AF: 0.768 AC: 1121764 AN: 1460744 Hom.: 433119 Cov.: 41 AF XY: 0.769 AC XY: 558870 AN XY: 726770

African (AFR) AF: 0.939 AC: 31403 AN: 33454

American (AMR) AF: 0.862 AC: 38527 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.785 AC: 20510 AN: 26130

East Asian (EAS) AF: 0.932 AC: 36979 AN: 39698

South Asian (SAS) AF: 0.846 AC: 72969 AN: 86230

European-Finnish (FIN) AF: 0.798 AC: 42601 AN: 53412

Middle Eastern (MID) AF: 0.726 AC: 4185 AN: 5768

European-Non Finnish (NFE) AF: 0.745 AC: 827430 AN: 1110970

Other (OTH) AF: 0.781 AC: 47160 AN: 60362

GnomAD4 genome AF: 0.822 AC: 125103 AN: 152182 Hom.: 51993 Cov.: 32 AF XY: 0.826 AC XY: 61468 AN XY: 74384

African (AFR) AF: 0.935 AC: 38857 AN: 41550

American (AMR) AF: 0.822 AC: 12562 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.789 AC: 2740 AN: 3472

East Asian (EAS) AF: 0.940 AC: 4872 AN: 5182

South Asian (SAS) AF: 0.858 AC: 4134 AN: 4816

European-Finnish (FIN) AF: 0.804 AC: 8510 AN: 10584

Middle Eastern (MID) AF: 0.772 AC: 227 AN: 294

European-Non Finnish (NFE) AF: 0.747 AC: 50778 AN: 67986

Other (OTH) AF: 0.833 AC: 1759 AN: 2112

Alfa AF: 0.755 Hom.: 29749

Bravo AF: 0.830

TwinsUK AF: 0.735 AC: 2724

ALSPAC AF: 0.750 AC: 2891

ESP6500AA AF: 0.938 AC: 3683

ESP6500EA AF: 0.762 AC: 6342

ExAC AF: 0.808 AC: 97627

Asia WGS AF: 0.898 AC: 3123 AN: 3478

EpiCase AF: 0.750

EpiControl AF: 0.754

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
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.72	T
BayesDel_noAF	Benign	-0.66
CADD	Benign	0.51
DANN	Benign	0.095
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.5
FATHMM_MKL	Benign	0.0029	N
LIST_S2	Benign	0.20	T
MetaRNN	Benign	0.0000016	T
MetaSVM	Benign	-0.98	T
PhyloP100		-0.68
PrimateAI	Benign	0.25	T
PROVEAN	Benign	-0.13	N
REVEL	Benign	0.095
Sift	Benign	0.67	T
Sift4G	Benign	0.45	T
Polyphen		0.0	B
Vest4		0.021
ClinPred		0.000031	T
GERP RS		-4.6
Mutation Taster		=99/1	polymorphism (auto)

Splicing

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

Other links and lift over

dbSNP: rs540825; hg19: chr6-154414446; COSMIC: COSV57676965; COSMIC: COSV57676965;