rs2131791254

Variant names:

• chr8-22148689-CA-C
• rs2131791254
• NM_139278.4:c.1117delT

Variant summary

Our verdict is Likely pathogenic. The variant received 8 ACMG points: 8P and 0B. PVS1_Strong PM2 PP5_Moderate

The NM_139278.4(LGI3):​c.1117delT​(p.Trp373GlyfsTer18) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: LGI3 NM_139278.4 frameshift
• Clinical Significance: Pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 9.32
• Publications: 0 publications found

Genes affected

LGI3 (HGNC:18711): (leucine rich repeat LGI family member 3) Predicted to enable catalytic activity. Predicted to be involved in regulation of exocytosis. Predicted to be located in extracellular region. Predicted to be active in synaptic vesicle. [provided by Alliance of Genome Resources, Apr 2022]

LGI3 Gene-Disease associations (from GenCC):

• intellectual developmental disorder with muscle tone abnormalities and distal skeletal defects

  Inheritance: AR, Unknown Classification: LIMITED Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Likely_pathogenic. The variant received 8 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. Fraction of 0.322 CDS is truncated, and there are 1 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 8-22148689-CA-C is Pathogenic according to our data. Variant chr8-22148689-CA-C is described in ClinVar as Pathogenic. ClinVar VariationId is 1699929.Status of the report is criteria_provided_single_submitter, 1 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_139278.4. 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
	LGI3	NM_139278.4	MANE Select	c.1117delT	p.Trp373GlyfsTer18	frameshift	Exon 8 of 8	NP_644807.1	Q8N145-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LGI3	ENST00000306317.7	TSL:1 MANE Select	c.1117delT	p.Trp373GlyfsTer18	frameshift	Exon 8 of 8	ENSP00000302297.2	Q8N145-1
	LGI3	ENST00000424267.6	TSL:1	c.1045delT	p.Trp349GlyfsTer18	frameshift	Exon 7 of 7	ENSP00000399121.2	Q8N145-2
	LGI3	ENST00000520124.5	TSL:1	n.2560delT		non_coding_transcript_exon	Exon 6 of 6

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
1	-	-	Intellectual developmental disorder with muscle tone abnormalities and distal skeletal defects (1)
1	-	-	Peripheral nerve hyperexcitability syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		9.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs2131791254; hg19: chr8-22006202;