10-93777401-G-T

Position:

• chr10-93777401-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP2

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.

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

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]

(HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), LGI1. . Gene score misZ 2.7809 (greater than the threshold 3.09). Trascript score misZ 3.4769 (greater than threshold 3.09). GenCC has associacion of gene with epilepsy, familial temporal lobe, 1, autosomal dominant epilepsy with auditory features.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LGI1	NM_005097.4	c.310G>T	p.Asp104Tyr	missense_variant	3/8	ENST00000371418.9	NP_005088.1
LOC105378437	XR_001747552.2	n.78-376C>A		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LGI1	ENST00000371418.9	c.310G>T	p.Asp104Tyr	missense_variant	3/8	1	NM_005097.4	ENSP00000360472	P1
	ENST00000627075.1	n.75-376C>A		intron_variant, non_coding_transcript_variant		3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

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;.;.;T;.
Eigen	Pathogenic	0.84
Eigen_PC	Pathogenic	0.87
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.91	D;D;.;D;D
M_CAP	Benign	0.049	D
MetaRNN	Uncertain	0.74	D;D;D;D;D
MetaSVM	Uncertain	0.64	D
MutationAssessor	Uncertain	2.3	M;.;.;.;M
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Pathogenic	0.83	D
PROVEAN	Uncertain	-2.8	D;.;.;.;D
REVEL	Uncertain	0.54
Sift	Benign	0.031	D;.;.;.;D
Sift4G	Uncertain	0.037	D;D;T;.;D
Polyphen		0.98	D;.;.;.;D
Vest4		0.67
MutPred		0.41		Gain of catalytic residue at D104 (P = 0.1491);.;Gain of catalytic residue at D104 (P = 0.1491);Gain of catalytic residue at D104 (P = 0.1491);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

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

Publications

LitVar

Other links and lift over

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