rs1799974

chr6-154091087-G-A

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 1P and 2B. PP3 BP4_Moderate

The NM_000914.5(OPRM1):c.779G>A(p.Arg260His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000977 in 1,614,096 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R260C) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00097 (1 hom., cov: 32)
  • Exomes 𝑓: 0.00098 (3 hom.)
• Consequence: OPRM1 NM_000914.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 10.0

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

Verdict is Likely_benign. Variant got -1 ACMG points.

• PP3: Multiple lines of computational evidence support a deleterious effect 8: AlphaMissense, Cadd, Dann, Eigen, FATHMM_MKL, phyloP100way_vertebrate, PrimateAI, PROVEAN [when BayesDel_addAF, max_spliceai, M_CAP, MetaRNN, MutationAssessor, MutationTaster was below the threshold]
• BP4: Computational evidence support a benign effect (MetaRNN=0.15125623).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
OPRM1	NM_000914.5	c.779G>A	p.Arg260His	missense_variant	3/4	ENST00000330432.12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
OPRM1	ENST00000330432.12	c.779G>A	p.Arg260His	missense_variant	3/4	1	NM_000914.5	P1

Frequencies

GnomAD3 genomes AF: 0.000973 AC: 148 AN: 152104 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.000483

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00321

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00166

Gnomad FIN AF: 0.0000944

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00101

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.000677 AC: 169 AN: 249576 Hom.: 1 AF XY: 0.000709 AC XY: 96 AN XY: 135406

Gnomad AFR exome AF: 0.000645

Gnomad AMR exome AF: 0.000869

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00173

Gnomad FIN exome AF: 0.0000464

Gnomad NFE exome AF: 0.000627

Gnomad OTH exome AF: 0.000659

GnomAD4 exome AF: 0.000978 AC: 1429 AN: 1461874 Hom.: 3 Cov.: 32 AF XY: 0.00103 AC XY: 746 AN XY: 727242

Gnomad4 AFR exome AF: 0.000777

Gnomad4 AMR exome AF: 0.00112

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000504

Gnomad4 SAS exome AF: 0.00147

Gnomad4 FIN exome AF: 0.0000936

Gnomad4 NFE exome AF: 0.00104

Gnomad4 OTH exome AF: 0.00101

GnomAD4 genome AF: 0.000972 AC: 148 AN: 152222 Hom.: 1 Cov.: 32 AF XY: 0.00103 AC XY: 77 AN XY: 74428

Gnomad4 AFR AF: 0.000482

Gnomad4 AMR AF: 0.00321

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00166

Gnomad4 FIN AF: 0.0000944

Gnomad4 NFE AF: 0.00101

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.000844 Hom.: 0

Bravo AF: 0.00105

TwinsUK AF: 0.000809 AC: 3

ALSPAC AF: 0.00130 AC: 5

ESP6500AA AF: 0.00115 AC: 5

ESP6500EA AF: 0.000816 AC: 7

ExAC AF: 0.000635 AC: 77

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00115

EpiControl AF: 0.000711

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.75
BayesDel_addAF	Benign	-0.071	T
BayesDel_noAF	Uncertain	0.11
Cadd	Pathogenic	33
Dann	Pathogenic	1.0
Eigen	Pathogenic	0.96
Eigen_PC	Pathogenic	0.96
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	1.0	D;.;D;D;D;D;D;D;D;D;D;D;D;.;D
M_CAP	Benign	0.042	D
MetaRNN	Benign	0.15	T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.77	T
MutationTaster	Benign	1.0	D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
PrimateAI	Pathogenic	0.86	D
PROVEAN	Pathogenic	-4.4	D;D;D;.;D;D;D;D;D;D;D;D;D;D;D
REVEL	Uncertain	0.43
Sift	Pathogenic	0.0	D;D;D;.;D;D;D;D;D;D;D;D;D;D;D
Sift4G	Benign	0.086	T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
Polyphen		1.0	D;.;.;.;D;D;D;D;D;D;D;D;D;.;.
Vest4		0.84
MVP		0.77
MPC		0.36
ClinPred		0.069	T
GERP RS		6.0
Varity_R		0.57
gMVP		0.88

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: rs1799974; hg19: chr6-154412222; COSMIC: COSV57673377; COSMIC: COSV57673377;