LGI4 p.Arg346Lys

Variant names:

• chr19-35126528-GCG-TTT
• NM_139284.3:c.1039_1041delCGCinsAAA
• LGI4 p.Arg347Lys

Your query was ambiguous. Multiple possible variants found:

• chr19-35126528-GCG-TTT
• chr19-35126528-GCG-CTT

Variant summary

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

The ENST00000874489.1(LGI4):​c.1036_1038delCGCinsAAA​(p.Arg346Lys) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. It is difficult to determine the true allele frequency of this variant because it is of type MNV, and the frequency of such variant types in population databases may be underestimated and unreliable. 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. R346C) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 33)
• Consequence: LGI4 ENST00000874489.1 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.13
• Publications: 0 publications found

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 Gene-Disease associations (from GenCC):

• arthrogryposis multiplex congenita 1, neurogenic, with myelin defect

  Inheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P
• hypomyelination neuropathy-arthrogryposis syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000874489.1. 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
	LGI4	NM_139284.3	MANE Select	c.1039_1041delCGCinsAAA	p.Arg347Lys	missense	N/A	NP_644813.1	Q8N135-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LGI4	ENST00000310123.8	TSL:1 MANE Select	c.1039_1041delCGCinsAAA	p.Arg347Lys	missense	N/A	ENSP00000312273.3	Q8N135-1
	LGI4	ENST00000587780.5	TSL:1	c.772_774delCGCinsAAA	p.Arg258Lys	missense	N/A	ENSP00000467044.2	K7ENQ0
	LGI4	ENST00000493050.5	TSL:1	n.1098_1100delCGCinsAAA		non_coding_transcript_exon	Exon 9 of 10

Frequencies

GnomAD3 genomes Cov.: 33

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

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		4.1

Splicing

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

hg19: chr19-35617432;