19-35125411-G-A

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.1396C>T(p.Leu466=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.361 in 1,608,600 control chromosomes in the GnomAD database, including 107,996 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.35 (9413 hom., cov: 32)
  • Exomes 𝑓: 0.36 (98583 hom.)
• Consequence: LGI4 NM_139284.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 3.12

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 (BayesDel_noAF=-0.55).
• BP6: Variant 19-35125411-G-A is Benign according to our data. Variant chr19-35125411-G-A is described in ClinVar as [Benign]. Clinvar id is 1243576.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=3.12 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.525 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LGI4	NM_139284.3	c.1396C>T	p.Leu466=	synonymous_variant	9/9	ENST00000310123.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LGI4	ENST00000310123.8	c.1396C>T	p.Leu466=	synonymous_variant	9/9	1	NM_139284.3	P1

Frequencies

GnomAD3 genomes AF: 0.348 AC: 52716 AN: 151638 Hom.: 9413 Cov.: 32

Gnomad AFR AF: 0.331

Gnomad AMI AF: 0.277

Gnomad AMR AF: 0.278

Gnomad ASJ AF: 0.393

Gnomad EAS AF: 0.244

Gnomad SAS AF: 0.543

Gnomad FIN AF: 0.398

Gnomad MID AF: 0.386

Gnomad NFE AF: 0.360

Gnomad OTH AF: 0.312

GnomAD3 exomes AF: 0.363 AC: 87675 AN: 241300 Hom.: 16656 AF XY: 0.377 AC XY: 49320 AN XY: 130766

Gnomad AFR exome AF: 0.325

Gnomad AMR exome AF: 0.258

Gnomad ASJ exome AF: 0.381

Gnomad EAS exome AF: 0.253

Gnomad SAS exome AF: 0.565

Gnomad FIN exome AF: 0.405

Gnomad NFE exome AF: 0.354

Gnomad OTH exome AF: 0.367

GnomAD4 exome AF: 0.363 AC: 528639 AN: 1456844 Hom.: 98583 Cov.: 43 AF XY: 0.370 AC XY: 268015 AN XY: 724218

Gnomad4 AFR exome AF: 0.323

Gnomad4 AMR exome AF: 0.258

Gnomad4 ASJ exome AF: 0.390

Gnomad4 EAS exome AF: 0.238

Gnomad4 SAS exome AF: 0.559

Gnomad4 FIN exome AF: 0.406

Gnomad4 NFE exome AF: 0.355

Gnomad4 OTH exome AF: 0.360

GnomAD4 genome AF: 0.348 AC: 52745 AN: 151756 Hom.: 9413 Cov.: 32 AF XY: 0.351 AC XY: 25996 AN XY: 74118

Gnomad4 AFR AF: 0.330

Gnomad4 AMR AF: 0.277

Gnomad4 ASJ AF: 0.393

Gnomad4 EAS AF: 0.244

Gnomad4 SAS AF: 0.542

Gnomad4 FIN AF: 0.398

Gnomad4 NFE AF: 0.360

Gnomad4 OTH AF: 0.313

Alfa AF: 0.358 Hom.: 4630

Bravo AF: 0.330

Asia WGS AF: 0.387 AC: 1345 AN: 3478

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_noAF	Benign	-0.55
Cadd	Benign	7.6
Dann	Benign	0.94

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: rs12610146; hg19: chr19-35616315; COSMIC: COSV59532541; COSMIC: COSV59532541;