Genetic Variant LGI3:p.Val510Met (chr8-22148279-C-T) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_139278.4(LGI3):c.1528G>A(p.Val510Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000558 in 1,614,030 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000055 ( 0 hom. )

Consequence

LGI3
NM_139278.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.48

Variant links:

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]

LGI3 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

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=0.22176272).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LGI3	NM_139278.4 link	c.1528G>A	p.Val510Met	missense_variant	Exon 8 of 8	ENST00000306317.7	NP_644807.1	Q8N145-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
LGI3	ENST00000306317.7 link	c.1528G>A	p.Val510Met	missense_variant	Exon 8 of 8	1	NM_139278.4	ENSP00000302297.2	Q8N145-1
LGI3	ENST00000424267.6 link	c.1456G>A	p.Val486Met	missense_variant	Exon 7 of 7	1		ENSP00000399121.2	Q8N145-2
LGI3	ENST00000520124.5 link	n.2971G>A		non_coding_transcript_exon_variant	Exon 6 of 6	1

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152188

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.00000547

AC:

AN:

1461842

Hom.:

Cov.:

AF XY:

0.00000550

AC XY:

AN XY:

727228

show subpopulations

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:

0.00000719

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152188

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74336

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Sep 22, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1528G>A (p.V510M) alteration is located in exon 8 (coding exon 8) of the LGI3 gene. This alteration results from a G to A substitution at nucleotide position 1528, causing the valine (V) at amino acid position 510 to be replaced by a methionine (M). 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

Uncertain

0.35

BayesDel_addAF

Benign

-0.10

BayesDel_noAF

Benign

-0.39

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Benign

0.29

T;.

Eigen

Benign

-0.14

Eigen_PC

Benign

0.033

FATHMM_MKL

Benign

0.64

LIST_S2

Uncertain

0.97

D;D

M_CAP

Benign

0.030

MetaRNN

Benign

0.22

T;T

MetaSVM

Benign

-0.42

MutationAssessor

Benign

0.55

N;.

PrimateAI

Uncertain

0.65

PROVEAN

Benign

-1.6

N;N

REVEL

Benign

0.20

Sift

Benign

0.075

T;T

Sift4G

Benign

0.12

T;T

Polyphen

0.15

B;.

Vest4

0.12

MutPred

0.43

Gain of MoRF binding (P = 0.2154);.;

MVP

0.79

MPC

0.29

ClinPred

0.78

GERP RS

5.1

Varity_R

0.097

gMVP

0.23

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over