10-93758145-A-T

Variant names:

• chr10-93758145-A-T
• rs202204627
• NM_005097.4:c.1A>T

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PVS1_Moderate PM2

The NM_005097.4(LGI1):​c.1A>T​(p.Met1?) variant causes a initiator codon change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,692 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: LGI1 NM_005097.4 initiator_codon
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.78
• Publications: 0 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)

ENSG00000303320 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

• PVS1: Start lost variant, next in-frame start position is after 1 pathogenic variants. Next in-frame start position is after 9 codons. Genomic position: 93758169. Lost 0.015 part of the original CDS.
• 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LGI1	NM_005097.4	MANE Select	c.1A>T	p.Met1?	initiator_codon	Exon 1 of 8	NP_005088.1	O95970-1
	LGI1	NM_001308276.2		c.1A>T	p.Met1?	initiator_codon	Exon 1 of 6	NP_001295205.1	O95970-3
	LGI1	NM_001308275.2		c.1A>T	p.Met1?	initiator_codon	Exon 1 of 8	NP_001295204.1	O95970-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LGI1	ENST00000371418.9	TSL:1 MANE Select	c.1A>T	p.Met1?	initiator_codon	Exon 1 of 8	ENSP00000360472.4	O95970-1
	LGI1	ENST00000371413.4	TSL:1	c.1A>T	p.Met1?	initiator_codon	Exon 1 of 8	ENSP00000360467.3	O95970-2
	LGI1	ENST00000627420.2	TSL:1	n.1A>T		non_coding_transcript_exon	Exon 1 of 6	ENSP00000487116.1	A0A0D9SFS5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461692 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 727152

African (AFR) AF: 0.00 AC: 0 AN: 33476

American (AMR) AF: 0.00 AC: 0 AN: 44710

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26132

East Asian (EAS) AF: 0.00 AC: 0 AN: 39696

South Asian (SAS) AF: 0.00 AC: 0 AN: 86252

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53414

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1111854

Other (OTH) AF: 0.00 AC: 0 AN: 60390

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Uncertain	0.026	T
BayesDel_noAF	Benign	-0.20
CADD	Benign	17
DANN	Benign	0.90
DEOGEN2	Benign	0.22	T
Eigen	Benign	-0.12
Eigen_PC	Benign	0.022
FATHMM_MKL	Benign	0.51	D
LIST_S2	Uncertain	0.90	D
M_CAP	Benign	0.074	D
MetaRNN	Pathogenic	0.93	D
MetaSVM	Benign	-0.74	T
PhyloP100		1.8
PROVEAN	Benign	-0.33	N
REVEL	Uncertain	0.32
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		0.0	B
Vest4		0.24
MutPred		0.98		Loss of MoRF binding (P = 0.182)
MVP		0.83
ClinPred		0.98	D
GERP RS		4.7
PromoterAI		0.066	Neutral
Varity_R		0.90
gMVP		0.58
Mutation Taster		=105/95	polymorphism

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

Other links and lift over

dbSNP: rs202204627; hg19: chr10-95517902;