chr20-64083831-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2PP3_Moderate

The NM_001353425.2(LKAAEAR1):ā€‹c.389A>Gā€‹(p.Tyr130Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000122 in 1,234,120 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: not found (cov: 33)
Exomes š‘“: 0.000012 ( 0 hom. )

Consequence

LKAAEAR1
NM_001353425.2 missense

Scores

4
9
5

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.06
Variant links:
Genes affected
LKAAEAR1 (HGNC:33718): (LKAAEAR motif containing 1)
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 4 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.855

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
LKAAEAR1NM_001353425.2 linkuse as main transcriptc.389A>G p.Tyr130Cys missense_variant 1/3 ENST00000302096.5 NP_001340354.1
OPRL1NM_182647.4 linkuse as main transcriptc.-185+3479T>C intron_variant ENST00000336866.7 NP_872588.1 P41146-1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
LKAAEAR1ENST00000302096.5 linkuse as main transcriptc.389A>G p.Tyr130Cys missense_variant 1/32 NM_001353425.2 ENSP00000302763.4 Q8TD35-1
OPRL1ENST00000336866.7 linkuse as main transcriptc.-185+3479T>C intron_variant 5 NM_182647.4 ENSP00000336843.2 P41146-1

Frequencies

GnomAD3 genomes
Cov.:
33
GnomAD4 exome
AF:
0.0000122
AC:
15
AN:
1234120
Hom.:
0
Cov.:
35
AF XY:
0.0000133
AC XY:
8
AN XY:
600528
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.0000139
Gnomad4 OTH exome
AF:
0.0000197
GnomAD4 genome
Cov.:
33
Bravo
AF:
0.00000756

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not specified Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingAmbry GeneticsOct 01, 2024The c.389A>G (p.Y130C) alteration is located in exon 1 (coding exon 1) of the LKAAEAR1 gene. This alteration results from a A to G substitution at nucleotide position 389, causing the tyrosine (Y) at amino acid position 130 to be replaced by a cysteine (C). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.69
BayesDel_addAF
Uncertain
0.12
D
BayesDel_noAF
Uncertain
-0.060
CADD
Pathogenic
27
DANN
Uncertain
1.0
DEOGEN2
Benign
0.18
.;T
Eigen
Uncertain
0.34
Eigen_PC
Uncertain
0.25
FATHMM_MKL
Benign
0.091
N
LIST_S2
Benign
0.64
T;T
M_CAP
Pathogenic
0.94
D
MetaRNN
Pathogenic
0.86
D;D
MetaSVM
Uncertain
-0.14
T
MutationAssessor
Uncertain
2.4
M;M
PROVEAN
Pathogenic
-8.7
D;D
REVEL
Benign
0.24
Sift
Uncertain
0.0040
D;D
Sift4G
Uncertain
0.021
D;D
Polyphen
1.0
D;.
Vest4
0.61
MVP
0.65
MPC
2.0
ClinPred
0.95
D
GERP RS
3.5
Varity_R
0.59
gMVP
0.10

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.

Other links and lift over

dbSNP: rs1448510843; hg19: chr20-62715184; API