19-35126303-GAACACGT-CTGGTGTG

Position:

• chr19-35126303-GAACACGT-CTGGTGTG

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_139284.3(LGI4):​c.1259_1266delACGTGTTCinsCACACCAG​(p.AspValPhe420AlaHisGln) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: LGI4 NM_139284.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.85

Genes affected

LGI4 (HGNC:18712): (leucine rich repeat LGI family member 4) Involved in regulation of myelination. Predicted to be located in extracellular region. Predicted to be active in extracellular space. Implicated in arthrogryposis multiplex congenita-1 and childhood absence epilepsy. [provided by Alliance of Genome Resources, Apr 2022]

LGI4 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LGI4	NM_139284.3	c.1259_1266delACGTGTTCinsCACACCAG	p.AspValPhe420AlaHisGln	missense_variant		ENST00000310123.8	NP_644813.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LGI4	ENST00000310123.8	c.1259_1266delACGTGTTCinsCACACCAG	p.AspValPhe420AlaHisGln	missense_variant		1	NM_139284.3	ENSP00000312273.3

Frequencies

GnomAD3 genomes Cov.: 32

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Arthrogryposis multiplex congenita 1, neurogenic, with myelin defect Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Neuberg Centre For Genomic Medicine, NCGM

-

The observed insertion/deletion (InDel) variant c.1259_1266delACGTGTTCinsCACACCAG (p.Asp420_Phe422delinsAlaHisGln) in LGI4 gene has not been reported previously as a pathogenic variant nor as a benign variant, to our knowledge. The p.Asp420_Phe422delinsAlaHisGln variant is absent in gnomAD Exomes databases. This variant has not been submitted to the ClinVar database. This variant causes a deletion of amino acid Aspartic Acid at position 420, Valine at position 421, and Phenylalanine at position 421, and causes an insertion of Alanine and Histidine at position 420, and an insertion of a Glutamine residue, that may create a premature Stop codon in the new reading frame. Loss of function variants in LGI4 gene have been previously reported to be disease causing. However, since this variant is present in the penultimate exon, functional studies will be required to prove protein truncation. Hence the variant is classified as a Variant of Uncertain Significance (VUS). In the absence of another reportable variant in the LGI4 gene, the molecular diagnosis is not confirmed. -

Computational scores

Source: dbNSFP v4.3

Splicing

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr19-35617207;