6-154011017-G-T

Position:

• chr6-154011017-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The ENST00000520282.5(OPRM1):​c.9G>T​(p.Gln3His) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 12/14 in silico tools predict a benign outcome for this variant. 2/2 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as drug response (no stars).

• Frequency: Genomes: not found (cov: 32)
• Consequence: OPRM1 ENST00000520282.5 missense, splice_region
• Scores: Splicing: ADA: 0.0004143
• Clinical Significance: drug response no assertion criteria provided O:1
• Conservation: PhyloP100: -0.666

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 Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.18273166).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
OPRM1	NM_001145279.4	c.-2G>T		splice_region_variant, 5_prime_UTR_variant	1/6
OPRM1	NM_001145280.4	c.-12G>T		splice_region_variant, 5_prime_UTR_variant	1/4
OPRM1	NM_001145281.3	c.47+458G>T		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
OPRM1	ENST00000520282.5	c.9G>T	p.Gln3His	missense_variant, splice_region_variant	1/3	1
OPRM1	ENST00000434900.6	c.-2G>T		splice_region_variant, 5_prime_UTR_variant	1/6	1
OPRM1	ENST00000520708.5	c.-12G>T		splice_region_variant, 5_prime_UTR_variant	1/4	1
OPRM1	ENST00000518759.5	c.47+458G>T		intron_variant		1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: drug response

Submissions summary: Other:1

Revision: no assertion criteria provided

Submissions by phenotype

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
BayesDel_addAF	Benign	-0.33	T
BayesDel_noAF	Benign	-0.72
CADD	Benign	0.42
DANN	Benign	0.31
Eigen	Benign	0.013
Eigen_PC	Benign	-0.42
FATHMM_MKL	Benign	0.054	N
LIST_S2	Benign	0.18	T
MetaRNN	Benign	0.18	T
MetaSVM	Benign	-0.92	T
MutationTaster	Benign	1.0	D;D;N
PROVEAN	Benign	-0.25	N
REVEL	Benign	0.034
Sift	Uncertain	0.0020	D
MutPred		0.22		Loss of disorder (P = 0.0662);
MVP		0.38
ClinPred		0.056	T
GERP RS		-1.8

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00041
dbscSNV1_RF	Benign	0.064

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

Publications

LitVar

Other links and lift over

dbSNP: rs1583106084; hg19: chr6-154332152;