Genetic Variant LKAAEAR1:p.Pro180His (chr20-64083569-G-T) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_001007125.3(LKAAEAR1):c.539C>A(p.Pro180His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000728 in 1,373,224 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P180L) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 7.3e-7 ( 0 hom. )

Consequence

LKAAEAR1
NM_001007125.3 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.0510

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:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001007125.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
OPRL1	NM_182647.4	MANE Select	c.-185+3217G>T		intron	N/A	NP_872588.1	P41146-1
LKAAEAR1	NM_001353425.2	MANE Select	c.525+14C>A		intron	N/A	NP_001340354.1	Q8TD35-1
LKAAEAR1	NM_001007125.3		c.539C>A	p.Pro180His	missense	Exon 2 of 2	NP_001007126.1	Q8TD35-2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
LKAAEAR1	ENST00000308906.6	TSL:1	c.539C>A	p.Pro180His	missense	Exon 2 of 2	ENSP00000310801.2	Q8TD35-2
OPRL1	ENST00000336866.7	TSL:5 MANE Select	c.-185+3217G>T		intron	N/A	ENSP00000336843.2	P41146-1
LKAAEAR1	ENST00000302096.5	TSL:2 MANE Select	c.525+14C>A		intron	N/A	ENSP00000302763.4	Q8TD35-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

7.28e-7

AC:

AN:

1373224

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

676306

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

30476

American (AMR)

AF:

0.00

AC:

AN:

31744

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

23400

East Asian (EAS)

AF:

0.00

AC:

AN:

35174

South Asian (SAS)

AF:

0.00

AC:

AN:

77784

European-Finnish (FIN)

AF:

0.00

AC:

AN:

44158

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5544

European-Non Finnish (NFE)

AF:

9.36e-7

AC:

AN:

1068218

Other (OTH)

AF:

0.00

AC:

AN:

56726

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.575

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.13

BayesDel_addAF

Benign

-0.20

BayesDel_noAF

Benign

-0.52

CADD

Benign

5.0

(source)

DANN

Uncertain

0.99

Eigen

Benign

-0.23

Eigen_PC

Benign

-0.46

FATHMM_MKL

Benign

0.014

LIST_S2

Benign

0.28

M_CAP

Benign

0.081

MetaRNN

Benign

0.19

MetaSVM

Benign

-0.99

PhyloP100

-0.051

PROVEAN

Benign

0.41

REVEL

Benign

0.12

Sift

Pathogenic

0.0

Sift4G

Pathogenic

0.0

Polyphen

1.0

Vest4

0.15

MutPred

0.087

Gain of helix (P = 0.0425)

MVP

0.28

MPC

1.7

ClinPred

0.43

GERP RS

2.2

gMVP

0.018

Mutation Taster

=90/10

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.23

Details are displayed if max score is > 0.2

DS_DG_spliceai

0.23

Position offset: -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

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over