chr6-154246692-G-A

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PVS1_StrongPM2PP3_Moderate

The ENST00000337049.8(OPRM1):​c.1165-1G>A variant causes a splice acceptor change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 1/1 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: 31)

Consequence

OPRM1
ENST00000337049.8 splice_acceptor

Scores

2
4
1

Clinical Significance

drug response no assertion criteria provided O:1

Conservation

PhyloP100: 6.43
Variant links:
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]
IPCEF1 (HGNC:21204): (interaction protein for cytohesin exchange factors 1) Predicted to enable peroxidase activity. Predicted to be involved in response to oxidative stress. Predicted to be located in cytosol and plasma membrane. [provided by Alliance of Genome Resources, Apr 2022]

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ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 8 ACMG points.

PVS1
Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.13842481 fraction of the gene. Cryptic splice site detected, with MaxEntScore 7.9, offset of -30, new splice context is: tttttccatttgttgcttAGgaa. Cryptic site results in inframe change. If cryptic site found is not functional and variant results in exon loss, it results in frameshift change.
PM2
Very rare variant in population databases, with high coverage;
PP3
BayesDel_addAF computational evidence supports a deleterious effect, 0.311

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
IPCEF1NM_001130700.2 linkuse as main transcriptc.145C>T p.Leu49= synonymous_variant 5/12 ENST00000367220.9

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
IPCEF1ENST00000367220.9 linkuse as main transcriptc.145C>T p.Leu49= synonymous_variant 5/122 NM_001130700.2 A2Q8WWN9-2

Frequencies

GnomAD3 genomes
Cov.:
31
GnomAD4 exome
Cov.:
31
GnomAD4 genome
Cov.:
31

ClinVar

Significance: drug response
Submissions summary: Other:1
Revision: no assertion criteria provided
LINK: link

Submissions by phenotype

Tramadol response Other:1
drug response, no assertion criteria providedresearchBruce Budowle Laboratory, University of North Texas Health Science CenterApr 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
Pathogenic
0.31
D
BayesDel_noAF
Pathogenic
0.21
CADD
Pathogenic
30
DANN
Uncertain
0.99
Eigen
Uncertain
0.40
Eigen_PC
Uncertain
0.48
FATHMM_MKL
Uncertain
0.89
D
MutationTaster
Benign
1.0
D;D;D;D;D
GERP RS
4.5

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

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs1583898985; hg19: chr6-154567826; API