rs62638690

Positions:

• chr6-154090110-G-T

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP4_Strong BP6_Moderate BS2

The NM_000914.5(OPRM1):​c.575G>T​(p.Cys192Phe) variant causes a missense change. The variant allele was found at a frequency of 0.00666 in 1,614,054 control chromosomes in the GnomAD database, including 47 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0054 (5 hom., cov: 32)
  • Exomes 𝑓: 0.0068 (42 hom.)
• Consequence: OPRM1 NM_000914.5 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1 O:1
• Conservation: PhyloP100: 6.69

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 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -10 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.012341559).
• BP6: Variant 6-154090110-G-T is Benign according to our data. Variant chr6-154090110-G-T is described in ClinVar as [Likely_benign]. Clinvar id is 828413.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High Homozygotes in GnomAd4 at 5 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
OPRM1	NM_000914.5	c.575G>T	p.Cys192Phe	missense_variant	2/4	ENST00000330432.12	NP_000905.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
OPRM1	ENST00000330432.12	c.575G>T	p.Cys192Phe	missense_variant	2/4	1	NM_000914.5	ENSP00000328264.7

Frequencies

GnomAD3 genomes AF: 0.00543 AC: 826 AN: 152146 Hom.: 5 Cov.: 32

Gnomad AFR AF: 0.000917

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00406

Gnomad ASJ AF: 0.0109

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.0190

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00712

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.00563 AC: 1400 AN: 248470 Hom.: 9 AF XY: 0.00559 AC XY: 754 AN XY: 134916

Gnomad AFR exome AF: 0.000775

Gnomad AMR exome AF: 0.000898

Gnomad ASJ exome AF: 0.0100

Gnomad EAS exome AF: 0.0000556

Gnomad SAS exome AF: 0.000850

Gnomad FIN exome AF: 0.0182

Gnomad NFE exome AF: 0.00724

Gnomad OTH exome AF: 0.00396

GnomAD4 exome AF: 0.00679 AC: 9930 AN: 1461790 Hom.: 42 Cov.: 32 AF XY: 0.00657 AC XY: 4777 AN XY: 727204

Gnomad4 AFR exome AF: 0.000836

Gnomad4 AMR exome AF: 0.000872

Gnomad4 ASJ exome AF: 0.0115

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.000719

Gnomad4 FIN exome AF: 0.0173

Gnomad4 NFE exome AF: 0.00734

Gnomad4 OTH exome AF: 0.00679

GnomAD4 genome AF: 0.00542 AC: 826 AN: 152264 Hom.: 5 Cov.: 32 AF XY: 0.00587 AC XY: 437 AN XY: 74446

Gnomad4 AFR AF: 0.000914

Gnomad4 AMR AF: 0.00406

Gnomad4 ASJ AF: 0.0109

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000415

Gnomad4 FIN AF: 0.0190

Gnomad4 NFE AF: 0.00712

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.00660 Hom.: 4

Bravo AF: 0.00392

TwinsUK AF: 0.00755 AC: 28

ALSPAC AF: 0.00804 AC: 31

ESP6500AA AF: 0.00122 AC: 5

ESP6500EA AF: 0.00792 AC: 67

ExAC AF: 0.00531 AC: 643

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00660

EpiControl AF: 0.00634

ClinVar

Significance: Likely benign

Submissions summary: Benign:1 Other:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Jan 01, 2023

OPRM1: BS2 -

Tramadol response Other:1

drug response, no assertion criteria provided

research

Bruce Budowle Laboratory, University of North Texas Health Science Center

Apr 28, 2018

- 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	0.14
BayesDel_addAF	Benign	-0.27	T
BayesDel_noAF	Benign	-0.16
CADD	Pathogenic	26
DANN	Uncertain	0.98
DEOGEN2	Benign	0.10	.;.;.;T;T;.;.;.;.;.;.;.;.;.;.
Eigen	Uncertain	0.46
Eigen_PC	Uncertain	0.58
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.93	D;.;D;D;D;D;D;D;D;D;D;D;D;.;D
MetaRNN	Benign	0.012	T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.89	T
MutationAssessor	Benign	1.1	.;.;.;.;L;L;L;L;L;L;L;L;L;.;.
PrimateAI	Pathogenic	0.79	T
PROVEAN	Pathogenic	-7.2	D;D;D;.;D;D;D;D;D;D;D;D;D;D;D
REVEL	Uncertain	0.33
Sift	Uncertain	0.0080	D;D;D;.;D;D;D;D;D;D;D;D;D;D;D
Sift4G	Uncertain	0.021	D;T;T;D;D;D;D;D;D;D;D;D;D;T;T
Polyphen		0.50	P;.;.;.;P;B;B;B;D;B;D;B;B;.;.
Vest4		0.56
MVP		0.86
MPC		0.19
ClinPred		0.032	T
GERP RS		5.8
Varity_R		0.84
gMVP		0.96

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

Publications

LitVar

Other links and lift over

dbSNP: rs62638690; hg19: chr6-154411245;