6-154093428-A-G

Variant names:

• chr6-154093428-A-G
• rs675026
• ENST00000229768.9:c.1323A>G

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.1323A>G​(p.Gly441Gly) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.681 in 1,612,778 control chromosomes in the GnomAD database, including 377,522 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 0.70 (37138 hom., cov: 31)
  • Exomes 𝑓: 0.68 (340384 hom.)
• Consequence: OPRM1 NM_001008505.2 synonymous
• Clinical Significance: drug response no assertion criteria provided O:1
• Conservation: PhyloP100: -0.315
• Publications: 40 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=-0.82).
• BP7: Synonymous conserved (PhyloP=-0.315 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+1956A>G		intron	N/A	NP_000905.3	P35372-1
	OPRM1	NM_001008505.2		c.1323A>G	p.Gly441Gly	synonymous	Exon 4 of 4	NP_001008505.2	P35372-3
	OPRM1	NM_001145279.4		c.1443+1956A>G		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.1323A>G	p.Gly441Gly	synonymous	Exon 4 of 4	ENSP00000229768.5	P35372-3
	OPRM1	ENST00000330432.12	TSL:1 MANE Select	c.1164+1956A>G		intron	N/A	ENSP00000328264.7	P35372-1
	OPRM1	ENST00000434900.6	TSL:1	c.1443+1956A>G		intron	N/A	ENSP00000394624.2	P35372-10

Frequencies

GnomAD3 genomes AF: 0.698 AC: 105623 AN: 151380 Hom.: 37125 Cov.: 31

Gnomad AFR AF: 0.723

Gnomad AMI AF: 0.596

Gnomad AMR AF: 0.742

Gnomad ASJ AF: 0.687

Gnomad EAS AF: 0.898

Gnomad SAS AF: 0.834

Gnomad FIN AF: 0.678

Gnomad MID AF: 0.718

Gnomad NFE AF: 0.652

Gnomad OTH AF: 0.729

GnomAD2 exomes AF: 0.720 AC: 179571 AN: 249392 AF XY: 0.721

Gnomad AFR exome AF: 0.726

Gnomad AMR exome AF: 0.778

Gnomad ASJ exome AF: 0.684

Gnomad EAS exome AF: 0.884

Gnomad FIN exome AF: 0.684

Gnomad NFE exome AF: 0.658

Gnomad OTH exome AF: 0.711

GnomAD4 exome AF: 0.680 AC: 993073 AN: 1461280 Hom.: 340384 Cov.: 45 AF XY: 0.683 AC XY: 496529 AN XY: 726974

African (AFR) AF: 0.727 AC: 24346 AN: 33474

American (AMR) AF: 0.775 AC: 34656 AN: 44714

Ashkenazi Jewish (ASJ) AF: 0.686 AC: 17932 AN: 26132

East Asian (EAS) AF: 0.891 AC: 35368 AN: 39690

South Asian (SAS) AF: 0.822 AC: 70928 AN: 86244

European-Finnish (FIN) AF: 0.683 AC: 36460 AN: 53402

Middle Eastern (MID) AF: 0.680 AC: 3920 AN: 5764

European-Non Finnish (NFE) AF: 0.655 AC: 727556 AN: 1111486

Other (OTH) AF: 0.694 AC: 41907 AN: 60374

GnomAD4 genome AF: 0.698 AC: 105683 AN: 151498 Hom.: 37138 Cov.: 31 AF XY: 0.703 AC XY: 52030 AN XY: 73998

African (AFR) AF: 0.722 AC: 29791 AN: 41252

American (AMR) AF: 0.741 AC: 11296 AN: 15234

Ashkenazi Jewish (ASJ) AF: 0.687 AC: 2381 AN: 3464

East Asian (EAS) AF: 0.898 AC: 4615 AN: 5142

South Asian (SAS) AF: 0.833 AC: 3993 AN: 4796

European-Finnish (FIN) AF: 0.678 AC: 7107 AN: 10488

Middle Eastern (MID) AF: 0.714 AC: 207 AN: 290

European-Non Finnish (NFE) AF: 0.652 AC: 44219 AN: 67824

Other (OTH) AF: 0.730 AC: 1535 AN: 2104

Alfa AF: 0.676 Hom.: 149451

Bravo AF: 0.707

Asia WGS AF: 0.855 AC: 2974 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	-0.82
CADD	Benign	0.31
DANN	Benign	0.43
PhyloP100		-0.32
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: rs675026; hg19: chr6-154414563; COSMIC: COSV57676970; COSMIC: COSV57676970;