rs17174638

chr6-154039434-C-T

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 2P and 8B. PM4 BA1

The ENST00000434900.6(OPRM1):c.169C>T(p.Gln57Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00576 in 1,551,464 control chromosomes in the GnomAD database, including 425 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. Synonymous variant affecting the same amino acid position (i.e. Q57Q) has been classified as Uncertain significance. Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: 𝑓 0.030 (211 hom., cov: 32)
  • Exomes 𝑓: 0.0031 (214 hom.)
• Consequence: OPRM1 ENST00000434900.6 stop_gained
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.63

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 -6 ACMG points.

• PM4: Stoplost variant in ENST00000434900.6 Downstream stopcodon found after 665 codons.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.101 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
OPRM1	NM_000914.5	c.-111C>T		5_prime_UTR_variant	1/4	ENST00000330432.12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
OPRM1	ENST00000330432.12	c.-111C>T		5_prime_UTR_variant	1/4	1	NM_000914.5	P1

Frequencies

GnomAD3 genomes AF: 0.0297 AC: 4512 AN: 152110 Hom.: 210 Cov.: 32

Gnomad AFR AF: 0.103

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0115

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000829

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000426

Gnomad OTH AF: 0.0172

GnomAD3 exomes AF: 0.00627 AC: 978 AN: 155892 Hom.: 39 AF XY: 0.00463 AC XY: 382 AN XY: 82460

Gnomad AFR exome AF: 0.0996

Gnomad AMR exome AF: 0.00530

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000183

Gnomad SAS exome AF: 0.000396

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000380

Gnomad OTH exome AF: 0.00457

GnomAD4 exome AF: 0.00314 AC: 4398 AN: 1399236 Hom.: 214 Cov.: 31 AF XY: 0.00276 AC XY: 1908 AN XY: 690116

Gnomad4 AFR exome AF: 0.103

Gnomad4 AMR exome AF: 0.00689

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000840

Gnomad4 SAS exome AF: 0.000581

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000281

Gnomad4 OTH exome AF: 0.00822

GnomAD4 genome AF: 0.0298 AC: 4531 AN: 152228 Hom.: 211 Cov.: 32 AF XY: 0.0286 AC XY: 2132 AN XY: 74452

Gnomad4 AFR AF: 0.103

Gnomad4 AMR AF: 0.0114

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000830

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000426

Gnomad4 OTH AF: 0.0189

Alfa AF: 0.00640 Hom.: 48

Bravo AF: 0.0334

ESP6500AA AF: 0.102 AC: 141

ESP6500EA AF: 0.000314 AC: 1

ExAC AF: 0.00386 AC: 342

Asia WGS AF: 0.0110 AC: 37 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.17	T
BayesDel_noAF	Uncertain	0.050
Cadd	Benign	0.0090
Dann	Uncertain	0.99
Eigen	Benign	-0.49
Eigen_PC	Benign	-0.89
FATHMM_MKL	Benign	0.00022	N
MutationTaster	Benign	1.0	A;N;N;N;N;N
Vest4		0.59, 0.76
GERP RS		-3.4

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: rs17174638; hg19: chr6-154360569;