chr20-64083615-C-T

Position:

• chr20-64083615-C-T

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_001353425.2(LKAAEAR1):​c.493G>A​(p.Ala165Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000454 in 1,322,172 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign 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 𝑓: 0.0000045 (0 hom.)
• Consequence: LKAAEAR1 NM_001353425.2 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.125

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]

ACMG classification

Verdict is Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.009739518).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LKAAEAR1	NM_001353425.2	c.493G>A	p.Ala165Thr	missense_variant	2/3	ENST00000302096.5	NP_001340354.1
OPRL1	NM_182647.4	c.-185+3263C>T		intron_variant		ENST00000336866.7	NP_872588.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LKAAEAR1	ENST00000302096.5	c.493G>A	p.Ala165Thr	missense_variant	2/3	2	NM_001353425.2	ENSP00000302763.4
OPRL1	ENST00000336866.7	c.-185+3263C>T		intron_variant		5	NM_182647.4	ENSP00000336843.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000454 AC: 6 AN: 1322172 Hom.: 0 Cov.: 38 AF XY: 0.00000618 AC XY: 4 AN XY: 647414

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: 0.00000573

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 09, 2024

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.052
BayesDel_addAF	Benign	-0.32	T
BayesDel_noAF	Benign	-0.70
CADD	Benign	17
DANN	Benign	0.97
DEOGEN2	Benign	0.0033	.;T
Eigen	Benign	-1.2
Eigen_PC	Benign	-0.95
FATHMM_MKL	Benign	0.00067	N
LIST_S2	Benign	0.23	T;T
M_CAP	Benign	0.023	T
MetaRNN	Benign	0.0097	T;T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	-2.2	N;N
PROVEAN	Benign	1.4	N;N
REVEL	Benign	0.12
Sift	Benign	1.0	T;T
Sift4G	Benign	1.0	T;T
Polyphen		0.0	B;.
Vest4		0.024
MutPred		0.085		Gain of glycosylation at A165 (P = 0.0085);Gain of glycosylation at A165 (P = 0.0085);
MVP		0.040
MPC		0.73
ClinPred		0.083	T
GERP RS		4.2
Varity_R		0.040
gMVP		0.015

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

Other links and lift over

dbSNP: rs1310619244; hg19: chr20-62714968;