Genetic Variant LGI1:p.Leu96Phe (chr10-93777379-G-T) – ACMG Classification: Uncertain_significance (3 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2PP3

The NM_005097.4(LGI1):c.288G>T(p.Leu96Phe) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. L96L) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 32)

Consequence

LGI1
NM_005097.4 missense, splice_region

Scores

Splicing: ADA: 0.9989

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.825

Publications

0 publications found

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 Gene-Disease associations (from GenCC):

autosomal dominant epilepsy with auditory features
Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: Orphanet, ClinGen
epilepsy, familial temporal lobe, 1
Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)

LGI1 links:

ENSG00000280485 (HGNC:):

ENSG00000280485 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF, max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005097.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
LGI1	NM_005097.4	MANE Select	c.288G>T	p.Leu96Phe	missense splice_region	Exon 3 of 8	NP_005088.1	O95970-1
LGI1	NM_001308275.2		c.288G>T	p.Leu96Phe	missense splice_region	Exon 3 of 8	NP_001295204.1	O95970-2
LGI1	NM_001308276.2		c.288-12720G>T		intron	N/A	NP_001295205.1	O95970-3

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
LGI1	ENST00000371418.9	TSL:1 MANE Select	c.288G>T	p.Leu96Phe	missense splice_region	Exon 3 of 8	ENSP00000360472.4	O95970-1
LGI1	ENST00000371413.4	TSL:1	c.288G>T	p.Leu96Phe	missense splice_region	Exon 3 of 8	ENSP00000360467.3	O95970-2
LGI1	ENST00000627420.2	TSL:1	n.*78-12720G>T		intron	N/A	ENSP00000487116.1	A0A0D9SFS5

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.98

BayesDel_addAF

Pathogenic

0.35

BayesDel_noAF

Pathogenic

0.26

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.87

Eigen

Pathogenic

0.72

Eigen_PC

Uncertain

0.63

FATHMM_MKL

Uncertain

0.86

LIST_S2

Pathogenic

1.0

M_CAP

Pathogenic

0.49

MetaRNN

Pathogenic

0.86

MetaSVM

Pathogenic

1.1

MutationAssessor

Pathogenic

4.3

PhyloP100

0.82

PrimateAI

Pathogenic

0.86

PROVEAN

Uncertain

-3.0

REVEL

Pathogenic

0.86

Sift

Uncertain

0.0020

Sift4G

Uncertain

0.0050

Polyphen

1.0

Vest4

0.85

MutPred

0.73

Loss of catalytic residue at L96 (P = 0.0931)

MVP

0.96

MPC

1.8

ClinPred

1.0

GERP RS

5.1

Varity_R

0.79

gMVP

0.79

Mutation Taster

=22/78

disease causing

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

1.0

dbscSNV1_RF

Pathogenic

0.92

SpliceAI score (max)

0.65

Details are displayed if max score is > 0.2

DS_AL_spliceai

0.65

Position offset: 0

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over