Genetic Variant NM_139284.3:c.863G>A (chr19-35126706-C-T) – ACMG Classification: Pathogenic (11 pts)

Variant summary

Our verdict is Pathogenic. The variant received 11 ACMG points: 11P and 0B. PVS1PM2PP5

The NM_139284.3(LGI4):c.863G>A(p.Trp288*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000361 in 1,386,186 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (no stars). Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0000036 ( 0 hom. )

Consequence

LGI4
NM_139284.3 stop_gained

Scores

Clinical Significance

Pathogenic no assertion criteria provided P:1

Conservation

PhyloP100: 1.97

Publications

0 publications found

Variant links:

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

LGI4 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 11 ACMG points.

PVS1

Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 19-35126706-C-T is Pathogenic according to our data. Variant chr19-35126706-C-T is described in ClinVar as Pathogenic. ClinVar VariationId is 424866.Status of the report is no_assertion_criteria_provided, 0 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_139284.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LGI4	NM_139284.3	MANE Select	c.863G>A	p.Trp288*	stop_gained	Exon 8 of 9	NP_644813.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
LGI4	ENST00000310123.8	TSL:1 MANE Select	c.863G>A	p.Trp288*	stop_gained	Exon 8 of 9	ENSP00000312273.3
LGI4	ENST00000587780.5	TSL:1	c.596G>A	p.Trp199*	stop_gained	Exon 6 of 6	ENSP00000467044.2
LGI4	ENST00000493050.5	TSL:1	n.922G>A		non_coding_transcript_exon	Exon 9 of 10

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000361

AC:

AN:

1386186

Hom.:

Cov.:

AF XY:

0.00000438

AC XY:

AN XY:

684194

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

31766

American (AMR)

AF:

0.00

AC:

AN:

35698

Ashkenazi Jewish (ASJ)

AF:

0.0000795

AC:

AN:

25142

East Asian (EAS)

AF:

0.00

AC:

AN:

35990

South Asian (SAS)

AF:

0.0000126

AC:

AN:

79262

European-Finnish (FIN)

AF:

0.00

AC:

AN:

35698

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5502

European-Non Finnish (NFE)

AF:

0.00000185

AC:

AN:

1079218

Other (OTH)

AF:

0.00

AC:

AN:

57910

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.505

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000756

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

LINK: link

Submissions by phenotype

Arthrogryposis multiplex congenita 1, neurogenic, with myelin defect

Pathogenic:1

Jul 15, 2025

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.19

BayesDel_addAF

Pathogenic

0.62

BayesDel_noAF

Benign

-0.18

CADD

Pathogenic

(source)

DANN

Uncertain

0.99

Eigen

Uncertain

0.46

Eigen_PC

Uncertain

0.27

FATHMM_MKL

Uncertain

0.86

LIST_S2

Benign

0.43

MetaRNN

Uncertain

0.48

MetaSVM

Benign

-0.75

PhyloP100

2.0

PROVEAN

Benign

-1.6

REVEL

Benign

0.26

Sift

Benign

0.10

Vest4

0.51

MutPred

0.15

Gain of MoRF binding (P = 0.0099)

MVP

0.85

ClinPred

0.98

GERP RS

3.3

Mutation Taster

=8/192

disease causing (ClinVar)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

Details are displayed if max score is > 0.2

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over