Genetic Variant LGI3:p.Gly384Ser (chr8-22148657-C-T) – ACMG Classification: Benign (-20 pts)

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_139278.4(LGI3):c.1150G>A(p.Gly384Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00272 in 1,614,014 control chromosomes in the GnomAD database, including 146 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.0046 ( 17 hom., cov: 32)

Exomes 𝑓: 0.0025 ( 129 hom. )

Consequence

LGI3
NM_139278.4 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: 3.14

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 Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0016196668).

BP6

Variant 8-22148657-C-T is Benign according to our data. Variant chr8-22148657-C-T is described in ClinVar as [Benign]. Clinvar id is 770570.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAdExome4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.0735 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LGI3	NM_139278.4 link	c.1150G>A	p.Gly384Ser	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.1150G>A	p.Gly384Ser	missense_variant	Exon 8 of 8	1	NM_139278.4	ENSP00000302297.2	Q8N145-1
LGI3	ENST00000424267.6 link	c.1078G>A	p.Gly360Ser	missense_variant	Exon 7 of 7	1		ENSP00000399121.2	Q8N145-2
LGI3	ENST00000520124.5 link	n.2593G>A		non_coding_transcript_exon_variant	Exon 6 of 6	1

Frequencies

GnomAD3 genomes

AF:

0.00460

AC:

700

AN:

152160

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00181

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0388

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000206

Gnomad OTH

AF:

0.00813

GnomAD3 exomes

AF:

0.0111

AC:

2796

AN:

251116

Hom.:

108

AF XY:

0.00855

AC XY:

1161

AN XY:

135760

show subpopulations

Gnomad AFR exome

AF:

0.00142

Gnomad AMR exome

AF:

0.0780

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000544

Gnomad SAS exome

AF:

0.000294

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000704

Gnomad OTH exome

AF:

0.00963

GnomAD4 exome

AF:

0.00252

AC:

3690

AN:

1461736

Hom.:

129

Cov.:

AF XY:

0.00220

AC XY:

1597

AN XY:

727168

show subpopulations

Gnomad4 AFR exome

AF:

0.000777

Gnomad4 AMR exome

AF:

0.0756

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.000151

Gnomad4 SAS exome

AF:

0.000429

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000585

Gnomad4 OTH exome

AF:

0.00288

GnomAD4 genome

AF:

0.00463

AC:

705

AN:

152278

Hom.:

Cov.:

AF XY:

0.00474

AC XY:

353

AN XY:

74476

show subpopulations

Gnomad4 AFR

AF:

0.00180

Gnomad4 AMR

AF:

0.0391

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000206

Gnomad4 OTH

AF:

0.00804

Alfa

AF:

0.000886

Hom.:

Bravo

AF:

0.00943

ESP6500AA

AF:

0.00159

AC:

ESP6500EA

AF:

0.000233

AC:

ExAC

AF:

0.00852

AC:

1034

Asia WGS

AF:

0.00144

AC:

AN:

3478

EpiCase

AF:

0.00

EpiControl

AF:

0.000119

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Jul 31, 2018

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.076

BayesDel_addAF

Benign

-0.38

BayesDel_noAF

Benign

-0.26

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Benign

0.12

T;.

Eigen

Benign

-0.12

Eigen_PC

Benign

-0.13

FATHMM_MKL

Benign

0.36

LIST_S2

Uncertain

0.93

D;D

MetaRNN

Benign

0.0016

T;T

MetaSVM

Benign

-0.55

MutationAssessor

Benign

0.0

N;.

PrimateAI

Benign

0.41

PROVEAN

Benign

1.4

N;N

REVEL

Benign

0.26

Sift

Uncertain

0.011

D;D

Sift4G

Uncertain

0.052

T;T

Polyphen

0.95

P;.

Vest4

0.18

MPC

0.33

ClinPred

0.034

GERP RS

5.1

Varity_R

0.092

gMVP

0.55

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