NM_005097.4:c.310G>T

Variant names:

• chr10-93777401-G-T
• rs145675377
• NM_005097.4:c.310G>T

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_005097.4(LGI1):​c.310G>T​(p.Asp104Tyr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D104N) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: LGI1 NM_005097.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 9.60
• Publications: 2 publications found

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)

ENSG00000280485 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LGI1	NM_005097.4	MANE Select	c.310G>T	p.Asp104Tyr	missense	Exon 3 of 8	NP_005088.1
	LGI1	NM_001308275.2		c.310G>T	p.Asp104Tyr	missense	Exon 3 of 8	NP_001295204.1
	LGI1	NM_001308276.2		c.288-12698G>T		intron	N/A	NP_001295205.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LGI1	ENST00000371418.9	TSL:1 MANE Select	c.310G>T	p.Asp104Tyr	missense	Exon 3 of 8	ENSP00000360472.4
	LGI1	ENST00000371413.4	TSL:1	c.310G>T	p.Asp104Tyr	missense	Exon 3 of 8	ENSP00000360467.3
	LGI1	ENST00000627420.2	TSL:1	n.*78-12698G>T		intron	N/A	ENSP00000487116.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.36
BayesDel_addAF	Pathogenic	0.26	D
BayesDel_noAF	Uncertain	0.13
CADD	Pathogenic	33
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.75	D
Eigen	Pathogenic	0.84
Eigen_PC	Pathogenic	0.87
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.91	D
M_CAP	Benign	0.049	D
MetaRNN	Uncertain	0.74	D
MetaSVM	Uncertain	0.64	D
MutationAssessor	Uncertain	2.3	M
PhyloP100		9.6
PrimateAI	Pathogenic	0.83	D
PROVEAN	Uncertain	-2.8	D
REVEL	Uncertain	0.54
Sift	Benign	0.031	D
Sift4G	Uncertain	0.037	D
Polyphen		0.98	D
Vest4		0.67
MutPred		0.41		Gain of catalytic residue at D104 (P = 0.1491)
MVP		0.78
MPC		1.9
ClinPred		0.99	D
GERP RS		6.2
Varity_R		0.52
gMVP		0.71
Mutation Taster		=6/94	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.19		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs145675377; hg19: chr10-95537158; COSMIC: COSV65057847; COSMIC: COSV65057847;