8-22148197-A-T

Variant names:

• chr8-22148197-A-T
• NM_139278.4:c.1610T>A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_139278.4(LGI3):​c.1610T>A​(p.Leu537Gln) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: LGI3 NM_139278.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.63

Genes affected

LGI3 (HGNC:18711): (leucine rich repeat LGI family member 3) Predicted to enable catalytic activity. Predicted to be involved in regulation of exocytosis. Predicted to be located in extracellular region. Predicted to be active in synaptic vesicle. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.2565629).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LGI3	NM_139278.4	c.1610T>A	p.Leu537Gln	missense_variant	Exon 8 of 8	ENST00000306317.7	NP_644807.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LGI3	ENST00000306317.7	c.1610T>A	p.Leu537Gln	missense_variant	Exon 8 of 8	1	NM_139278.4	ENSP00000302297.2
LGI3	ENST00000424267.6	c.1538T>A	p.Leu513Gln	missense_variant	Exon 7 of 7	1		ENSP00000399121.2
LGI3	ENST00000520124.5	n.3053T>A		non_coding_transcript_exon_variant	Exon 6 of 6	1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Mar 05, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1610T>A (p.L537Q) alteration is located in exon 8 (coding exon 8) of the LGI3 gene. This alteration results from a T to A substitution at nucleotide position 1610, causing the leucine (L) at amino acid position 537 to be replaced by a glutamine (Q). 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	0.075
BayesDel_addAF	Uncertain	0.023	T
BayesDel_noAF	Benign	-0.20
CADD	Benign	22
DANN	Benign	0.096
DEOGEN2	Benign	0.12	T;.
Eigen	Benign	-0.065
Eigen_PC	Benign	-0.058
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.86	D;T
M_CAP	Benign	0.061	D
MetaRNN	Benign	0.26	T;T
MetaSVM	Benign	-0.57	T
MutationAssessor	Benign	-0.63	N;.
PrimateAI	Uncertain	0.67	T
PROVEAN	Benign	2.4	N;N
REVEL	Uncertain	0.40
Sift	Benign	0.94	T;T
Sift4G	Benign	0.97	T;T
Polyphen		1.0	D;.
Vest4		0.34
MutPred		0.51		Gain of methylation at K533 (P = 0.069);.;
MVP		0.91
MPC		0.86
ClinPred		0.72	D
GERP RS		4.8
Varity_R		0.14
gMVP		0.58

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr8-22005710;