chr19-35126706-C-T

Position:

• chr19-35126706-C-T

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PVS1_Strong PM2 PP5

The ENST00000310123.8(LGI4):​c.863G>A​(p.Trp288Ter) 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).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000036 (0 hom.)
• Consequence: LGI4 ENST00000310123.8 stop_gained
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 1.97

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]

ACMG classification

Verdict is Likely_pathogenic. Variant got 7 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most 50 bp of the penultimate exon, not predicted to undergo nonsense mediated mRNA decay. There are 6 pathogenic variants in the truncated region.
• 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 id is 424866.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LGI4	NM_139284.3	c.863G>A	p.Trp288Ter	stop_gained	8/9	ENST00000310123.8	NP_644813.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LGI4	ENST00000310123.8	c.863G>A	p.Trp288Ter	stop_gained	8/9	1	NM_139284.3	ENSP00000312273	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000361 AC: 5 AN: 1386186 Hom.: 0 Cov.: 59 AF XY: 0.00000438 AC XY: 3 AN XY: 684194

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.0000795

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000126

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000185

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000756

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

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

Pathogenic, no assertion criteria provided

literature only

OMIM

Jul 30, 2020

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.62	D
BayesDel_noAF	Benign	-0.18
CADD	Pathogenic	38
DANN	Uncertain	0.99
Eigen	Uncertain	0.46
Eigen_PC	Uncertain	0.27
FATHMM_MKL	Uncertain	0.86	D
LIST_S2	Benign	0.43	T
MetaRNN	Uncertain	0.48	T
MetaSVM	Benign	-0.75	T
MutationTaster	Benign	1.0	A;D;D
PROVEAN	Benign	-1.6	N
REVEL	Benign	0.26
Sift	Benign	0.10	T
Vest4		0.51
MutPred		0.15		Gain of MoRF binding (P = 0.0099);
MVP		0.85
ClinPred		0.98	D
GERP RS		3.3

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

LitVar

Other links and lift over

dbSNP: rs775997446; hg19: chr19-35617610; COSMIC: COSV104402289; COSMIC: COSV104402289;