10-93758145-A-G

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 8P and 9B. PVS1BP6BS1BS2

The NM_005097.4(LGI1):c.1A>G(p.Met1?) variant causes a start lost change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000491 in 1,614,034 control chromosomes in the GnomAD database, including 7 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00077 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00046 ( 7 hom. )

Consequence

LGI1
NM_005097.4 start_lost

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:5

Conservation

PhyloP100: 1.78

Variant links:

Genes affected

LGI1 (HGNC:6572): (leucine rich glioma inactivated 1) This gene encodes a member of the secreted leucine-rich repeat (LRR) superfamily and shares homology with members of the SLIT protein family. The encoded protein may regulate the activity of voltage-gated potassium channels and may be involved in neuronal growth regulation and cell survival. This gene is rearranged as a result of translocations in glioblastoma cell lines, and it is frequently down-regulated or rearranged in malignant gliomas. Mutations in this gene result in autosomal dominant lateral temporal epilepsy. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Apr 2015]

LGI1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -1 ACMG points.

PVS1

Start lost variant, no new inframe start found.

BP6

Variant 10-93758145-A-G is Benign according to our data. Variant chr10-93758145-A-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 415035.We mark this variant Likely_benign, oryginal submissions are: {Benign=2, Likely_benign=3, Uncertain_significance=1}.

BS1

Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.000775 (118/152342) while in subpopulation EAS AF= 0.000965 (5/5180). AF 95% confidence interval is 0.00038. There are 0 homozygotes in gnomad4. There are 76 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High AC in GnomAd at 118 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LGI1	NM_005097.4 linkuse as main transcript	c.1A>G	p.Met1?	start_lost	1/8	ENST00000371418.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LGI1	ENST00000371418.9 linkuse as main transcript	c.1A>G	p.Met1?	start_lost	1/8	1	NM_005097.4	P1	O95970-1

Frequencies

GnomAD3 genomes

AF:

0.000775

AC:

118

AN:

152224

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000121

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000963

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00734

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000397

Gnomad OTH

AF:

0.000955

GnomAD3 exomes

AF:

0.00105

AC:

264

AN:

251302

Hom.:

AF XY:

0.000891

AC XY:

121

AN XY:

135838

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000289

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000327

Gnomad FIN exome

AF:

0.00693

Gnomad NFE exome

AF:

0.000871

Gnomad OTH exome

AF:

0.00212

GnomAD4 exome

AF:

0.000462

AC:

675

AN:

1461692

Hom.:

Cov.:

AF XY:

0.000458

AC XY:

333

AN XY:

727152

show subpopulations

Gnomad4 AFR exome

AF:

0.000209

Gnomad4 AMR exome

AF:

0.0000224

Gnomad4 ASJ exome

AF:

0.0000383

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.0000464

Gnomad4 FIN exome

AF:

0.00749

Gnomad4 NFE exome

AF:

0.000187

Gnomad4 OTH exome

AF:

0.000878

GnomAD4 genome

AF:

0.000775

AC:

118

AN:

152342

Hom.:

Cov.:

AF XY:

0.00102

AC XY:

AN XY:

74494

show subpopulations

Gnomad4 AFR

AF:

0.000120

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000965

Gnomad4 SAS

AF:

0.000207

Gnomad4 FIN

AF:

0.00734

Gnomad4 NFE

AF:

0.000397

Gnomad4 OTH

AF:

0.000945

Alfa

AF:

0.000838

Hom.:

Bravo

AF:

0.000181

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000233

AC:

ExAC

AF:

0.00109

AC:

132

Asia WGS

AF:

0.000866

AC:

AN:

3478

EpiCase

AF:

0.000109

EpiControl

AF:

0.000178

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:5

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Benign:2

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Oct 16, 2020	This variant is associated with the following publications: (PMID: 26993267) -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Dec 01, 2022	LGI1: BS1 -

Epilepsy, familial temporal lobe, 1

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

not specified

Benign:1

Benign, criteria provided, single submitter

clinical testing

Athena Diagnostics

Nov 08, 2019

- -

Autosomal dominant epilepsy with auditory features

Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 18, 2024

- -

LGI1-related disorder

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Aug 26, 2020

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Benign

-0.24

BayesDel_noAF

Benign

-0.13

Cadd

Benign

Dann

Benign

0.97

DEOGEN2

Benign

0.24

T;.;.;.;.;T;T;.

Eigen

Benign

-0.12

Eigen_PC

Benign

0.022

FATHMM_MKL

Benign

0.59

LIST_S2

Uncertain

0.90

D;D;.;.;D;D;D;D

M_CAP

Uncertain

0.11

MetaRNN

Benign

0.012

T;T;T;T;T;T;T;T

MetaSVM

Benign

-0.74

MutationTaster

Benign

1.0

N;N;N

PROVEAN

Benign

-0.48

N;.;.;.;.;.;.;N

REVEL

Uncertain

0.32

Sift

Pathogenic

0.0

D;.;.;.;.;.;.;D

Sift4G

Pathogenic

0.0

D;D;D;D;D;.;D;D

Polyphen

0.0

B;.;.;.;B;.;.;B

Vest4

0.35

MVP

0.89

ClinPred

0.18

GERP RS

4.7

Varity_R

0.90

gMVP

0.68

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