19-35125444-C-T

Variant names:

• chr19-35125444-C-T
• rs201144421
• NM_139284.3:c.1363G>A

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PM2 BP4_Strong BS1_Supporting

The NM_139284.3(LGI4):​c.1363G>A​(p.Val455Ile) variant causes a missense change. The variant allele was found at a frequency of 0.000356 in 1,604,948 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00032 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00036 (1 hom.)
• Consequence: LGI4 NM_139284.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.67

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_benign. Variant got -3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.029977232).
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.000322 (49/152254) while in subpopulation NFE AF= 0.000618 (42/68002). AF 95% confidence interval is 0.000469. There are 0 homozygotes in gnomad4. There are 20 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LGI4	NM_139284.3	c.1363G>A	p.Val455Ile	missense_variant	Exon 9 of 9	ENST00000310123.8	NP_644813.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LGI4	ENST00000310123.8	c.1363G>A	p.Val455Ile	missense_variant	Exon 9 of 9	1	NM_139284.3	ENSP00000312273.3

Frequencies

GnomAD3 genomes AF: 0.000322 AC: 49 AN: 152136 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000724

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000618

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.000219 AC: 51 AN: 233232 Hom.: 0 AF XY: 0.000197 AC XY: 25 AN XY: 126874

Gnomad AFR exome AF: 0.000136

Gnomad AMR exome AF: 0.000185

Gnomad ASJ exome AF: 0.000105

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000363

Gnomad OTH exome AF: 0.000703

GnomAD4 exome AF: 0.000359 AC: 522 AN: 1452694 Hom.: 1 Cov.: 36 AF XY: 0.000335 AC XY: 242 AN XY: 721716

Gnomad4 AFR exome AF: 0.0000599

Gnomad4 AMR exome AF: 0.000139

Gnomad4 ASJ exome AF: 0.000232

Gnomad4 EAS exome AF: 0.0000762

Gnomad4 SAS exome AF: 0.0000117

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000447

Gnomad4 OTH exome AF: 0.000150

GnomAD4 genome AF: 0.000322 AC: 49 AN: 152254 Hom.: 0 Cov.: 32 AF XY: 0.000269 AC XY: 20 AN XY: 74446

Gnomad4 AFR AF: 0.0000722

Gnomad4 AMR AF: 0.000131

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000618

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.000333 Hom.: 0

Bravo AF: 0.000261

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000519 AC: 2

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000582 AC: 5

ExAC AF: 0.000148 AC: 18

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Oct 17, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1363G>A (p.V455I) alteration is located in exon 9 (coding exon 9) of the LGI4 gene. This alteration results from a G to A substitution at nucleotide position 1363, causing the valine (V) at amino acid position 455 to be replaced by an isoleucine (I). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.081
BayesDel_addAF	Benign	-0.31	T
BayesDel_noAF	Benign	-0.36
CADD	Benign	21
DANN	Uncertain	0.99
DEOGEN2	Benign	0.17	T
Eigen	Benign	-0.35
Eigen_PC	Benign	-0.23
FATHMM_MKL	Benign	0.75	D
LIST_S2	Uncertain	0.87	D
M_CAP	Benign	0.061	D
MetaRNN	Benign	0.030	T
MetaSVM	Benign	-0.77	T
MutationAssessor	Benign	0.52	N
PrimateAI	Benign	0.48	T
PROVEAN	Benign	-0.61	N
REVEL	Benign	0.15
Sift	Benign	0.12	T
Sift4G	Benign	0.17	T
Polyphen		0.056	B
Vest4		0.10
MVP		0.54
MPC		0.31
ClinPred		0.038	T
GERP RS		1.2
Varity_R		0.055
gMVP		0.43

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: rs201144421; hg19: chr19-35616348;