chr20-64083910-C-T

Position:

• chr20-64083910-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.310G>A​(p.Ala104Thr) 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. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: LKAAEAR1 NM_001353425.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.196

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=0.039640993).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LKAAEAR1	NM_001353425.2	c.310G>A	p.Ala104Thr	missense_variant	1/3	ENST00000302096.5
OPRL1	NM_182647.4	c.-185+3558C>T		intron_variant		ENST00000336866.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LKAAEAR1	ENST00000302096.5	c.310G>A	p.Ala104Thr	missense_variant	1/3	2	NM_001353425.2	P1
OPRL1	ENST00000336866.7	c.-185+3558C>T		intron_variant		5	NM_182647.4	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1294498 Hom.: 0 Cov.: 35 AF XY: 0.00 AC XY: 0 AN XY: 634960

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: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 23, 2023

The c.310G>A (p.A104T) alteration is located in exon 1 (coding exon 1) of the LKAAEAR1 gene. This alteration results from a G to A substitution at nucleotide position 310, causing the alanine (A) at amino acid position 104 to be replaced by a threonine (T). 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	Benign	0.078
BayesDel_addAF	Benign	-0.35	T
BayesDel_noAF	Benign	-0.74
CADD	Benign	8.6
DANN	Benign	0.93
DEOGEN2	Benign	0.017	.;T
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.5
FATHMM_MKL	Benign	0.075	N
LIST_S2	Benign	0.39	T;T
M_CAP	Uncertain	0.22	D
MetaRNN	Benign	0.040	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.90	L;L
MutationTaster	Benign	1.0	N;N;N;N
PROVEAN	Benign	-0.40	N;N
REVEL	Benign	0.0080
Sift	Benign	0.36	T;T
Sift4G	Benign	0.52	T;T
Polyphen		0.086	B;.
Vest4		0.045
MutPred		0.093		Gain of phosphorylation at A104 (P = 0.0444);Gain of phosphorylation at A104 (P = 0.0444);
MVP		0.030
MPC		0.76
ClinPred		0.018	T
GERP RS		-1.6
Varity_R		0.039
gMVP		0.024

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs1281216299; hg19: chr20-62715263;