Genetic Variant NM_000914.5:c.197C>T (chr6-154039741-C-T) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_000914.5(OPRM1):c.197C>T(p.Ser66Phe) variant causes a missense change. The variant allele was found at a frequency of 0.0000416 in 1,609,098 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in UniProt.

Frequency

Genomes: 𝑓 0.000053 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000041 ( 0 hom. )

Consequence

OPRM1
NM_000914.5 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 4.70

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]

OPRM1 links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.15628555).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
OPRM1	NM_000914.5 link	c.197C>T	p.Ser66Phe	missense_variant	Exon 1 of 4	ENST00000330432.12	NP_000905.3	P35372-1G8XRH5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
OPRM1	ENST00000330432.12 link	c.197C>T	p.Ser66Phe	missense_variant	Exon 1 of 4	1	NM_000914.5	ENSP00000328264.7		P35372-1

Frequencies

GnomAD3 genomes

AF:

0.0000526

AC:

AN:

152198

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000118

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000693

AC:

AN:

245366

Hom.:

AF XY:

0.0000974

AC XY:

AN XY:

133464

show subpopulations

Gnomad AFR exome

AF:

0.0000647

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000327

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000531

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000405

AC:

AN:

1456782

Hom.:

Cov.:

AF XY:

0.0000497

AC XY:

AN XY:

724906

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000301

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000270

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

AF:

0.0000525

AC:

AN:

152316

Hom.:

Cov.:

AF XY:

0.0000671

AC XY:

AN XY:

74478

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000118

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000399

Hom.:

Bravo

AF:

0.0000264

ExAC

AF:

0.0000909

AC:

EpiCase

AF:

0.000218

EpiControl

AF:

0.000178

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.41

BayesDel_addAF

Benign

-0.080

BayesDel_noAF

Uncertain

-0.050

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Benign

0.022

.;.;T;T;.;.;.;.;.;.;.;.

Eigen

Benign

0.18

Eigen_PC

Uncertain

0.35

FATHMM_MKL

Benign

0.061

LIST_S2

Uncertain

0.87

D;D;D;D;D;D;D;D;D;D;D;D

M_CAP

Benign

0.014

MetaRNN

Benign

0.16

T;T;T;T;T;T;T;T;T;T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.69

.;.;.;N;N;N;N;N;N;N;N;N

PrimateAI

Uncertain

0.57

PROVEAN

Uncertain

-2.6

D;N;.;N;N;N;N;N;N;N;N;N

REVEL

Benign

0.22

Sift

Uncertain

0.0010

D;D;.;D;D;D;D;D;D;D;D;D

Sift4G

Uncertain

0.035

D;T;T;T;T;T;T;T;T;T;T;T

Polyphen

0.51, 0.023, 0.039, 0.99, 0.97, 0.27

.;P;.;B;B;D;P;D;B;D;B;B

Vest4

0.27, 0.30, 0.31, 0.30, 0.33, 0.32, 0.34, 0.34, 0.30, 0.34

MutPred

0.17

.;.;.;Loss of disorder (P = 0.0054);Loss of disorder (P = 0.0054);Loss of disorder (P = 0.0054);Loss of disorder (P = 0.0054);Loss of disorder (P = 0.0054);Loss of disorder (P = 0.0054);Loss of disorder (P = 0.0054);Loss of disorder (P = 0.0054);Loss of disorder (P = 0.0054);

MVP

0.41

MPC

0.096

ClinPred

0.30

GERP RS

5.8

Varity_R

0.22

gMVP

0.66

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

LitVar

Other links and lift over