6-154093438-C-T

Variant names:

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

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP7 BA1

The NM_001008505.2(OPRM1):​c.1333C>T​(p.Leu445Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.676 in 1,612,816 control chromosomes in the GnomAD database, including 371,452 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as drug response (no stars).

• Frequency:
  • Genomes: 𝑓 0.67 (34184 hom., cov: 31)
  • Exomes 𝑓: 0.68 (337268 hom.)
• Consequence: OPRM1 NM_001008505.2 synonymous
• Clinical Significance: drug response no assertion criteria provided O:1
• 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: Benign. The variant received -13 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.79).
• BP7: Synonymous conserved (PhyloP=0.386 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.876 is higher than 0.05.

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>T		intron	N/A	NP_000905.3	P35372-1
	OPRM1	NM_001008505.2		c.1333C>T	p.Leu445Leu	synonymous	Exon 4 of 4	NP_001008505.2	P35372-3
	OPRM1	NM_001145279.4		c.1443+1966C>T		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>T	p.Leu445Leu	synonymous	Exon 4 of 4	ENSP00000229768.5	P35372-3
	OPRM1	ENST00000330432.12	TSL:1 MANE Select	c.1164+1966C>T		intron	N/A	ENSP00000328264.7	P35372-1
	OPRM1	ENST00000434900.6	TSL:1	c.1443+1966C>T		intron	N/A	ENSP00000394624.2	P35372-10

Frequencies

GnomAD3 genomes AF: 0.669 AC: 101319 AN: 151418 Hom.: 34180 Cov.: 31

Gnomad AFR AF: 0.624

Gnomad AMI AF: 0.596

Gnomad AMR AF: 0.730

Gnomad ASJ AF: 0.688

Gnomad EAS AF: 0.898

Gnomad SAS AF: 0.833

Gnomad FIN AF: 0.678

Gnomad MID AF: 0.715

Gnomad NFE AF: 0.652

Gnomad OTH AF: 0.706

GnomAD2 exomes AF: 0.713 AC: 177718 AN: 249284 AF XY: 0.716

Gnomad AFR exome AF: 0.629

Gnomad AMR exome AF: 0.773

Gnomad ASJ exome AF: 0.684

Gnomad EAS exome AF: 0.884

Gnomad FIN exome AF: 0.684

Gnomad NFE exome AF: 0.657

Gnomad OTH exome AF: 0.707

GnomAD4 exome AF: 0.676 AC: 988529 AN: 1461280 Hom.: 337268 Cov.: 44 AF XY: 0.680 AC XY: 494529 AN XY: 726968

African (AFR) AF: 0.629 AC: 21065 AN: 33468

American (AMR) AF: 0.770 AC: 34411 AN: 44704

Ashkenazi Jewish (ASJ) AF: 0.686 AC: 17933 AN: 26132

East Asian (EAS) AF: 0.891 AC: 35360 AN: 39686

South Asian (SAS) AF: 0.820 AC: 70738 AN: 86226

European-Finnish (FIN) AF: 0.683 AC: 36447 AN: 53384

Middle Eastern (MID) AF: 0.670 AC: 3859 AN: 5760

European-Non Finnish (NFE) AF: 0.654 AC: 727245 AN: 1111538

Other (OTH) AF: 0.687 AC: 41471 AN: 60382

GnomAD4 genome AF: 0.669 AC: 101357 AN: 151536 Hom.: 34184 Cov.: 31 AF XY: 0.676 AC XY: 50008 AN XY: 74006

African (AFR) AF: 0.623 AC: 25710 AN: 41260

American (AMR) AF: 0.730 AC: 11127 AN: 15252

Ashkenazi Jewish (ASJ) AF: 0.688 AC: 2383 AN: 3466

East Asian (EAS) AF: 0.897 AC: 4611 AN: 5138

South Asian (SAS) AF: 0.832 AC: 4000 AN: 4806

European-Finnish (FIN) AF: 0.678 AC: 7109 AN: 10492

Middle Eastern (MID) AF: 0.710 AC: 206 AN: 290

European-Non Finnish (NFE) AF: 0.652 AC: 44185 AN: 67818

Other (OTH) AF: 0.705 AC: 1487 AN: 2110

Alfa AF: 0.665 Hom.: 102497

Bravo AF: 0.675

Asia WGS AF: 0.844 AC: 2934 AN: 3478

EpiCase AF: 0.662

EpiControl AF: 0.668

ClinVar

ClinVar submissions

Significance: drug response

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
-	-	-	Tramadol response (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.79
CADD	Benign	14
DANN	Benign	0.62
PhyloP100		0.39
Mutation Taster		=100/0	polymorphism (auto)

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; COSMIC: COSV57676979; COSMIC: COSV57676979;