rs1448510843

Variant names:

• chr20-64083831-T-C
• rs1448510843
• NM_001353425.2:c.389A>G

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_001353425.2(LKAAEAR1):​c.389A>G​(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. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.000012 (0 hom.)
• Consequence: LKAAEAR1 NM_001353425.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.06
• Publications: 0 publications found

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

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

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

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LKAAEAR1	NM_001353425.2	MANE Select	c.389A>G	p.Tyr130Cys	missense	Exon 1 of 3	NP_001340354.1	Q8TD35-1
	OPRL1	NM_182647.4	MANE Select	c.-185+3479T>C		intron	N/A	NP_872588.1	P41146-1
	LKAAEAR1	NM_001007125.3		c.389A>G	p.Tyr130Cys	missense	Exon 1 of 2	NP_001007126.1	Q8TD35-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LKAAEAR1	ENST00000302096.5	TSL:2 MANE Select	c.389A>G	p.Tyr130Cys	missense	Exon 1 of 3	ENSP00000302763.4	Q8TD35-1
	LKAAEAR1	ENST00000308906.6	TSL:1	c.389A>G	p.Tyr130Cys	missense	Exon 1 of 2	ENSP00000310801.2	Q8TD35-2
	OPRL1	ENST00000336866.7	TSL:5 MANE Select	c.-185+3479T>C		intron	N/A	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

African (AFR) AF: 0.00 AC: 0 AN: 24270

American (AMR) AF: 0.00 AC: 0 AN: 12658

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 18644

East Asian (EAS) AF: 0.00 AC: 0 AN: 27208

South Asian (SAS) AF: 0.00 AC: 0 AN: 57804

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 30106

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3598

European-Non Finnish (NFE) AF: 0.0000139 AC: 14 AN: 1008942

Other (OTH) AF: 0.0000197 AC: 1 AN: 50890

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000756

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

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
M_CAP	Pathogenic	0.94	D
MetaRNN	Pathogenic	0.86	D
MetaSVM	Uncertain	-0.14	T
MutationAssessor	Uncertain	2.4	M
PhyloP100		2.1
PROVEAN	Pathogenic	-8.7	D
REVEL	Benign	0.24
Sift	Uncertain	0.0040	D
Sift4G	Uncertain	0.021	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
Mutation Taster		=90/10	polymorphism

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

Other links and lift over

dbSNP: rs1448510843; hg19: chr20-62715184;