ENST00000434900.6:c.-384T>A

Variant names:

• chr6-154010635-T-A
• rs115788842
• ENST00000434900.6:c.-384T>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The ENST00000434900.6(OPRM1):​c.-384T>A variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0216 in 1,498,774 control chromosomes in the GnomAD database, including 1,057 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 0.026 (196 hom., cov: 32)
  • Exomes 𝑓: 0.021 (861 hom.)
• Consequence: OPRM1 ENST00000434900.6 5_prime_UTR
• Clinical Significance: drug response no assertion criteria provided O:1
• Conservation: PhyloP100: 1.16
• Publications: 3 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.74).
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.126 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
OPRM1	NM_001145279.4	c.-384T>A		5_prime_UTR_variant	Exon 1 of 6		NP_001138751.1
OPRM1	NM_001145280.4	c.-394T>A		5_prime_UTR_variant	Exon 1 of 4		NP_001138752.1
OPRM1	NM_001145281.3	c.47+76T>A		intron_variant	Intron 1 of 3		NP_001138753.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
OPRM1	ENST00000434900.6	c.-384T>A		5_prime_UTR_variant	Exon 1 of 6	1		ENSP00000394624.2
OPRM1	ENST00000520708.5	c.-394T>A		5_prime_UTR_variant	Exon 1 of 4	1		ENSP00000430876.1
OPRM1	ENST00000520282.5	c.-374T>A		5_prime_UTR_variant	Exon 1 of 3	1		ENSP00000430247.1
OPRM1	ENST00000518759.5	c.47+76T>A		intron_variant	Intron 1 of 3	1		ENSP00000430260.1

Frequencies

GnomAD3 genomes AF: 0.0262 AC: 3989 AN: 152042 Hom.: 187 Cov.: 32

Gnomad AFR AF: 0.00980

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.129

Gnomad ASJ AF: 0.0363

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.0176

Gnomad FIN AF: 0.0176

Gnomad MID AF: 0.0222

Gnomad NFE AF: 0.0165

Gnomad OTH AF: 0.0436

GnomAD4 exome AF: 0.0211 AC: 28428 AN: 1346614 Hom.: 861 Cov.: 30 AF XY: 0.0210 AC XY: 13793 AN XY: 656852

African (AFR) AF: 0.00936 AC: 278 AN: 29690

American (AMR) AF: 0.188 AC: 5613 AN: 29810

Ashkenazi Jewish (ASJ) AF: 0.0305 AC: 713 AN: 23384

East Asian (EAS) AF: 0.000115 AC: 4 AN: 34796

South Asian (SAS) AF: 0.0277 AC: 2034 AN: 73442

European-Finnish (FIN) AF: 0.0199 AC: 927 AN: 46536

Middle Eastern (MID) AF: 0.0160 AC: 87 AN: 5440

European-Non Finnish (NFE) AF: 0.0166 AC: 17419 AN: 1047946

Other (OTH) AF: 0.0243 AC: 1353 AN: 55570

GnomAD4 genome AF: 0.0264 AC: 4012 AN: 152160 Hom.: 196 Cov.: 32 AF XY: 0.0273 AC XY: 2028 AN XY: 74404

African (AFR) AF: 0.00975 AC: 405 AN: 41556

American (AMR) AF: 0.130 AC: 1989 AN: 15266

Ashkenazi Jewish (ASJ) AF: 0.0363 AC: 126 AN: 3470

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5170

South Asian (SAS) AF: 0.0176 AC: 85 AN: 4816

European-Finnish (FIN) AF: 0.0176 AC: 187 AN: 10602

Middle Eastern (MID) AF: 0.0238 AC: 7 AN: 294

European-Non Finnish (NFE) AF: 0.0165 AC: 1121 AN: 67964

Other (OTH) AF: 0.0431 AC: 91 AN: 2110

Alfa AF: 0.0217 Hom.: 17

Bravo AF: 0.0371

Asia WGS AF: 0.0180 AC: 62 AN: 3478

ClinVar

Significance: drug response

Submissions summary: Other:1

Revision: no assertion criteria provided

Submissions by phenotype

Tramadol response Other:1

Apr 28, 2018

Bruce Budowle Laboratory, University of North Texas Health Science Center

Significance: drug response

Review Status: no assertion criteria provided

Collection Method: research

- 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_noAF	Benign	-0.74
CADD	Benign	7.3
DANN	Benign	0.78
PhyloP100		1.2
PromoterAI		0.032	Neutral
Mutation Taster		=299/1	polymorphism (auto)

Splicing

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

Other links and lift over

dbSNP: rs115788842; hg19: chr6-154331770;