chr6-154039373-G-T

Variant names:

• chr6-154039373-G-T
• rs6912029
• ENST00000360422.8:c.15G>T

Variant summary

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

The ENST00000360422.8(OPRM1):​c.15G>T​(p.Gln5His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.05 in 1,545,042 control chromosomes in the GnomAD database, including 2,416 homozygotes. In-silico tool predicts a benign outcome for this variant. 9/10 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as drug response (no stars).

• Frequency:
  • Genomes: 𝑓 0.061 (397 hom., cov: 32)
  • Exomes 𝑓: 0.049 (2019 hom.)
• Consequence: OPRM1 ENST00000360422.8 missense
• Clinical Significance: drug response no assertion criteria provided O:1
• Conservation: PhyloP100: 0.376
• Publications: 37 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=0.001701355).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.109 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
OPRM1	NM_000914.5	c.-172G>T		5_prime_UTR_variant	Exon 1 of 4	ENST00000330432.12	NP_000905.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
OPRM1	ENST00000330432.12	c.-172G>T		5_prime_UTR_variant	Exon 1 of 4	1	NM_000914.5	ENSP00000328264.7

Frequencies

GnomAD3 genomes AF: 0.0609 AC: 9260 AN: 152122 Hom.: 392 Cov.: 32

Gnomad AFR AF: 0.111

Gnomad AMI AF: 0.0669

Gnomad AMR AF: 0.0255

Gnomad ASJ AF: 0.00894

Gnomad EAS AF: 0.0943

Gnomad SAS AF: 0.0574

Gnomad FIN AF: 0.0298

Gnomad MID AF: 0.0158

Gnomad NFE AF: 0.0439

Gnomad OTH AF: 0.0435

GnomAD2 exomes AF: 0.0441 AC: 6666 AN: 151002 AF XY: 0.0448

Gnomad AFR exome AF: 0.115

Gnomad AMR exome AF: 0.0147

Gnomad ASJ exome AF: 0.00989

Gnomad EAS exome AF: 0.0948

Gnomad FIN exome AF: 0.0323

Gnomad NFE exome AF: 0.0433

Gnomad OTH exome AF: 0.0362

GnomAD4 exome AF: 0.0488 AC: 67934 AN: 1392802 Hom.: 2019 Cov.: 31 AF XY: 0.0488 AC XY: 33478 AN XY: 686016

African (AFR) AF: 0.119 AC: 3754 AN: 31468

American (AMR) AF: 0.0166 AC: 588 AN: 35344

Ashkenazi Jewish (ASJ) AF: 0.00895 AC: 221 AN: 24688

East Asian (EAS) AF: 0.0943 AC: 3359 AN: 35616

South Asian (SAS) AF: 0.0510 AC: 3995 AN: 78394

European-Finnish (FIN) AF: 0.0317 AC: 1554 AN: 49066

Middle Eastern (MID) AF: 0.0181 AC: 102 AN: 5650

European-Non Finnish (NFE) AF: 0.0480 AC: 51620 AN: 1074896

Other (OTH) AF: 0.0475 AC: 2741 AN: 57680

GnomAD4 genome AF: 0.0609 AC: 9269 AN: 152240 Hom.: 397 Cov.: 32 AF XY: 0.0599 AC XY: 4462 AN XY: 74438

African (AFR) AF: 0.112 AC: 4637 AN: 41548

American (AMR) AF: 0.0253 AC: 387 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.00894 AC: 31 AN: 3468

East Asian (EAS) AF: 0.0937 AC: 484 AN: 5164

South Asian (SAS) AF: 0.0566 AC: 273 AN: 4824

European-Finnish (FIN) AF: 0.0298 AC: 316 AN: 10608

Middle Eastern (MID) AF: 0.0170 AC: 5 AN: 294

European-Non Finnish (NFE) AF: 0.0439 AC: 2983 AN: 68014

Other (OTH) AF: 0.0435 AC: 92 AN: 2114

Alfa AF: 0.0480 Hom.: 678

Bravo AF: 0.0633

TwinsUK AF: 0.0507 AC: 188

ALSPAC AF: 0.0519 AC: 200

ESP6500AA AF: 0.107 AC: 148

ESP6500EA AF: 0.0409 AC: 130

ExAC AF: 0.0230 AC: 1206

Asia WGS AF: 0.0770 AC: 270 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
AlphaMissense	Benign	0.15
BayesDel_addAF	Benign	-0.68	T
BayesDel_noAF	Benign	-0.65
CADD	Benign	7.9
DANN	Benign	0.64
DEOGEN2	Benign	0.0050	T
FATHMM_MKL	Benign	0.0011	N
LIST_S2	Benign	0.40	T
MetaRNN	Benign	0.0017	T
PhyloP100		0.38
Vest4		0.17
GERP RS		3.9
PromoterAI		-0.0084	Neutral
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: rs6912029; hg19: chr6-154360508; COSMIC: COSV107214359; COSMIC: COSV107214359;