6-154093438-C-A

Variant names:

• chr6-154093438-C-A
• rs562859
• ENST00000229768.9:c.1333C>A

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001008505.2(OPRM1):​c.1333C>A​(p.Leu445Met) variant causes a missense 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. 15/18 in silico tools predict 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. L445L) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 31)
• Consequence: OPRM1 NM_001008505.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.386
• Publications: 41 publications found

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

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.17546052).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001008505.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	OPRM1	NM_000914.5	MANE Select	c.1164+1966C>A		intron	N/A	NP_000905.3	P35372-1
	OPRM1	NM_001008505.2		c.1333C>A	p.Leu445Met	missense	Exon 4 of 4	NP_001008505.2	P35372-3
	OPRM1	NM_001145279.4		c.1443+1966C>A		intron	N/A	NP_001138751.1	P35372-10

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	OPRM1	ENST00000229768.9	TSL:1	c.1333C>A	p.Leu445Met	missense	Exon 4 of 4	ENSP00000229768.5	P35372-3
	OPRM1	ENST00000330432.12	TSL:1 MANE Select	c.1164+1966C>A		intron	N/A	ENSP00000328264.7	P35372-1
	OPRM1	ENST00000434900.6	TSL:1	c.1443+1966C>A		intron	N/A	ENSP00000394624.2	P35372-10

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 44

GnomAD4 genome Cov.: 31

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Benign	-0.11	T
BayesDel_noAF	Benign	-0.40
CADD	Benign	13
DANN	Benign	0.92
Eigen	Benign	-0.42
Eigen_PC	Benign	-0.52
FATHMM_MKL	Benign	0.087	N
LIST_S2	Benign	0.31	T
M_CAP	Benign	0.055	D
MetaRNN	Benign	0.18	T
MetaSVM	Benign	-0.61	T
PhyloP100		0.39
PrimateAI	Benign	0.30	T
PROVEAN	Benign	-0.020	N
REVEL	Benign	0.15
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		0.69	P
Vest4		0.26
MutPred		0.20		Gain of phosphorylation at S446 (P = 0.2092)
MVP		0.59
ClinPred		0.20	T
GERP RS		3.7
Mutation Taster		=96/4	polymorphism

Splicing

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

Other links and lift over

dbSNP: rs562859; hg19: chr6-154414573;