Genetic Variant ENST00000229768.9:c.1206A>T (chr6-154093311-A-T) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_StrongBA1

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. 12/14 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

Scores

Clinical Significance

drug response no assertion criteria provided O:1

Conservation

PhyloP100: -0.683

Variant links:

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]

OPRM1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -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 link	c.1164+1839A>T		intron_variant	Intron 3 of 3	ENST00000330432.12	NP_000905.3	P35372-1G8XRH5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
OPRM1	ENST00000330432.12 link	c.1164+1839A>T		intron_variant	Intron 3 of 3	1	NM_000914.5	ENSP00000328264.7		P35372-1

Frequencies

GnomAD3 genomes

AF:

0.822

AC:

124996

AN:

152066

Hom.:

51942

Cov.:

show subpopulations

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

GnomAD3 exomes

AF:

0.809

AC:

201769

AN:

249428

Hom.:

82340

AF XY:

0.805

AC XY:

108909

AN XY:

135314

show subpopulations

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 SAS exome

AF:

0.850

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.:

AF XY:

0.769

AC XY:

558870

AN XY:

726770

show subpopulations

Gnomad4 AFR exome

AF:

0.939

Gnomad4 AMR exome

AF:

0.862

Gnomad4 ASJ exome

AF:

0.785

Gnomad4 EAS exome

AF:

0.932

Gnomad4 SAS exome

AF:

0.846

Gnomad4 FIN exome

AF:

0.798

Gnomad4 NFE exome

AF:

0.745

Gnomad4 OTH exome

AF:

0.781

GnomAD4 genome

AF:

0.822

AC:

125103

AN:

152182

Hom.:

51993

Cov.:

AF XY:

0.826

AC XY:

61468

AN XY:

74384

show subpopulations

Gnomad4 AFR

AF:

0.935

Gnomad4 AMR

AF:

0.822

Gnomad4 ASJ

AF:

0.789

Gnomad4 EAS

AF:

0.940

Gnomad4 SAS

AF:

0.858

Gnomad4 FIN

AF:

0.804

Gnomad4 NFE

AF:

0.747

Gnomad4 OTH

AF:

0.833

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

LINK: link

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_addAF

Benign

-0.72

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

LIST_S2

Benign

0.20

MetaRNN

Benign

0.0000016

MetaSVM

Benign

-0.98

PrimateAI

Benign

0.25

PROVEAN

Benign

-0.13

REVEL

Benign

0.095

Sift

Benign

0.67

Sift4G

Benign

0.45

Polyphen

0.0

Vest4

0.021

ClinPred

0.000031

GERP RS

-4.6

Splicing

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over