19-35126366-T-C

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_139284.3(LGI4):c.1203A>G(p.Thr401=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.363 in 1,610,242 control chromosomes in the GnomAD database, including 109,251 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.36 (9915 hom., cov: 32)
  • Exomes 𝑓: 0.36 (99336 hom.)
• Consequence: LGI4 NM_139284.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -4.39

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 Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=3.8878046E-5).
• BP6: Variant 19-35126366-T-C is Benign according to our data. Variant chr19-35126366-T-C is described in ClinVar as [Benign]. Clinvar id is 1247001.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-4.39 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.531 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LGI4	NM_139284.3	c.1203A>G	p.Thr401=	synonymous_variant	8/9	ENST00000310123.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LGI4	ENST00000310123.8	c.1203A>G	p.Thr401=	synonymous_variant	8/9	1	NM_139284.3	P1

Frequencies

GnomAD3 genomes AF: 0.355 AC: 54001 AN: 151930 Hom.: 9915 Cov.: 32

Gnomad AFR AF: 0.353

Gnomad AMI AF: 0.281

Gnomad AMR AF: 0.281

Gnomad ASJ AF: 0.394

Gnomad EAS AF: 0.245

Gnomad SAS AF: 0.549

Gnomad FIN AF: 0.403

Gnomad MID AF: 0.386

Gnomad NFE AF: 0.361

Gnomad OTH AF: 0.317

GnomAD3 exomes AF: 0.363 AC: 87222 AN: 240086 Hom.: 16854 AF XY: 0.377 AC XY: 49183 AN XY: 130626

Gnomad AFR exome AF: 0.342

Gnomad AMR exome AF: 0.257

Gnomad ASJ exome AF: 0.381

Gnomad EAS exome AF: 0.251

Gnomad SAS exome AF: 0.568

Gnomad FIN exome AF: 0.403

Gnomad NFE exome AF: 0.352

Gnomad OTH exome AF: 0.364

GnomAD4 exome AF: 0.364 AC: 530570 AN: 1458194 Hom.: 99336 Cov.: 49 AF XY: 0.371 AC XY: 268924 AN XY: 725024

Gnomad4 AFR exome AF: 0.346

Gnomad4 AMR exome AF: 0.259

Gnomad4 ASJ exome AF: 0.389

Gnomad4 EAS exome AF: 0.237

Gnomad4 SAS exome AF: 0.563

Gnomad4 FIN exome AF: 0.405

Gnomad4 NFE exome AF: 0.355

Gnomad4 OTH exome AF: 0.362

GnomAD4 genome AF: 0.355 AC: 54029 AN: 152048 Hom.: 9915 Cov.: 32 AF XY: 0.359 AC XY: 26645 AN XY: 74300

Gnomad4 AFR AF: 0.353

Gnomad4 AMR AF: 0.280

Gnomad4 ASJ AF: 0.394

Gnomad4 EAS AF: 0.245

Gnomad4 SAS AF: 0.548

Gnomad4 FIN AF: 0.403

Gnomad4 NFE AF: 0.361

Gnomad4 OTH AF: 0.318

Alfa AF: 0.332 Hom.: 4595

Bravo AF: 0.337

TwinsUK AF: 0.356 AC: 1319

ALSPAC AF: 0.359 AC: 1382

ESP6500AA AF: 0.355 AC: 1566

ESP6500EA AF: 0.357 AC: 3066

ExAC AF: 0.363 AC: 43972

Asia WGS AF: 0.389 AC: 1354 AN: 3476

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

May 04, 2021

- -

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

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Aug 19, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.41	T
BayesDel_noAF	Benign	-0.22
Cadd	Benign	0.34
Dann	Benign	0.62
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.5
FATHMM_MKL	Benign	0.040	N
LIST_S2	Benign	0.22	T
MetaRNN	Benign	0.000039	T
MetaSVM	Benign	-0.96	T
MutationTaster	Benign	1.0	P;P;P
PROVEAN	Benign	-0.11	N
REVEL	Benign	0.17
Sift	Pathogenic	0.0	D
Vest4		0.022
ClinPred		0.020	T
GERP RS		-9.0

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: rs1319969; hg19: chr19-35617270; COSMIC: COSV59534456; COSMIC: COSV59534456;