Genetic Variant LKAAEAR1:p.Pro86Leu (chr20-64083963-G-A) – ACMG Classification: Likely_benign (-4 pts)

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 2P and 6B. PM2BP4_StrongBP6_Moderate

The NM_001353425.2(LKAAEAR1):c.257C>T(p.Pro86Leu) 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. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

LKAAEAR1
NM_001353425.2 missense

Scores

Clinical Significance

Likely benign criteria provided, single submitter B:1

Conservation

PhyloP100: 0.841

Publications

0 publications found

Variant links:

Genes affected

LKAAEAR1 (HGNC:33718): (LKAAEAR motif containing 1)

LKAAEAR1 links:

OPRL1 (HGNC:8155): (opioid related nociceptin receptor 1) The protein encoded by this gene is a member of the 7 transmembrane-spanning G protein-coupled receptor family, and functions as a receptor for the endogenous, opioid-related neuropeptide, nociceptin/orphanin FQ. This receptor-ligand system modulates a variety of biological functions and neurobehavior, including stress responses and anxiety behavior, learning and memory, locomotor activity, and inflammatory and immune responses. A promoter region between this gene and the 5'-adjacent RGS19 (regulator of G-protein signaling 19) gene on the opposite strand functions bi-directionally as a core-promoter for both genes, suggesting co-operative transcriptional regulation of these two functionally related genes. Alternatively spliced transcript variants have been described for this gene. A recent study provided evidence for translational readthrough in this gene, and expression of an additional C-terminally extended isoform via the use of an alternative in-frame translation termination codon. [provided by RefSeq, Dec 2017]

OPRL1 links:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -4 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.0317131).

BP6

Variant 20-64083963-G-A is Benign according to our data. Variant chr20-64083963-G-A is described in ClinVar as Likely_benign. ClinVar VariationId is 2604425.Status of the report is criteria_provided_single_submitter, 1 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001353425.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
LKAAEAR1	NM_001353425.2	MANE Select	c.257C>T	p.Pro86Leu	missense	Exon 1 of 3	NP_001340354.1	Q8TD35-1
OPRL1	NM_182647.4	MANE Select	c.-185+3611G>A		intron	N/A	NP_872588.1	P41146-1
LKAAEAR1	NM_001007125.3		c.257C>T	p.Pro86Leu	missense	Exon 1 of 2	NP_001007126.1	Q8TD35-2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
LKAAEAR1	ENST00000302096.5	TSL:2 MANE Select	c.257C>T	p.Pro86Leu	missense	Exon 1 of 3	ENSP00000302763.4	Q8TD35-1
LKAAEAR1	ENST00000308906.6	TSL:1	c.257C>T	p.Pro86Leu	missense	Exon 1 of 2	ENSP00000310801.2	Q8TD35-2
OPRL1	ENST00000336866.7	TSL:5 MANE Select	c.-185+3611G>A		intron	N/A	ENSP00000336843.2	P41146-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

1316242

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

647886

African (AFR)

AF:

0.00

AC:

AN:

26498

American (AMR)

AF:

0.00

AC:

AN:

26096

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

22742

East Asian (EAS)

AF:

0.00

AC:

AN:

28366

South Asian (SAS)

AF:

0.00

AC:

AN:

72000

European-Finnish (FIN)

AF:

0.00

AC:

AN:

32562

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4078

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1049358

Other (OTH)

AF:

0.00

AC:

AN:

54542

GnomAD4 genome

Cov.:

ClinVar

ClinVar submissions

Significance:Likely benign

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.072

BayesDel_addAF

Benign

-0.35

BayesDel_noAF

Benign

-0.74

CADD

Benign

6.4

(source)

DANN

Benign

0.89

DEOGEN2

Benign

0.0017

Eigen

Benign

-1.3

Eigen_PC

Benign

-1.2

FATHMM_MKL

Benign

0.0047

LIST_S2

Benign

0.52

M_CAP

Benign

0.040

MetaRNN

Benign

0.032

MetaSVM

Benign

-1.0

MutationAssessor

Benign

-1.4

PhyloP100

0.84

PROVEAN

Benign

1.7

REVEL

Benign

0.036

Sift

Benign

0.55

Sift4G

Benign

0.58

Polyphen

0.0010

Vest4

0.070

MutPred

0.27

Loss of disorder (P = 0.0132)

MVP

0.072

MPC

0.77

ClinPred

0.039

GERP RS

2.1

PromoterAI

-0.018

Neutral

(source)

Varity_R

0.024

gMVP

0.013

Mutation Taster

=100/0

polymorphism

(source)

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over