19-35125412-C-T

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.1395G>A(p.Gln465=) 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 1,608,378 control chromosomes in the GnomAD database, including 107,999 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.35 (9415 hom., cov: 32)
  • Exomes 𝑓: 0.36 (98584 hom.)
• Consequence: LGI4 NM_139284.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 2.30

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=2.2032857E-4).
• BP6: Variant 19-35125412-C-T is Benign according to our data. Variant chr19-35125412-C-T is described in ClinVar as [Benign]. Clinvar id is 1272294.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=2.3 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.526 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LGI4	NM_139284.3	c.1395G>A	p.Gln465=	synonymous_variant	9/9	ENST00000310123.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LGI4	ENST00000310123.8	c.1395G>A	p.Gln465=	synonymous_variant	9/9	1	NM_139284.3	P1

Frequencies

GnomAD3 genomes AF: 0.348 AC: 52724 AN: 151596 Hom.: 9415 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: 0.544

Gnomad FIN AF: 0.398

Gnomad MID AF: 0.386

Gnomad NFE AF: 0.360

Gnomad OTH AF: 0.312

GnomAD3 exomes AF: 0.364 AC: 87702 AN: 241074 Hom.: 16671 AF XY: 0.378 AC XY: 49333 AN XY: 130680

Gnomad AFR exome AF: 0.326

Gnomad AMR exome AF: 0.258

Gnomad ASJ exome AF: 0.382

Gnomad EAS exome AF: 0.254

Gnomad SAS exome AF: 0.565

Gnomad FIN exome AF: 0.406

Gnomad NFE exome AF: 0.354

Gnomad OTH exome AF: 0.367

GnomAD4 exome AF: 0.363 AC: 528644 AN: 1456664 Hom.: 98584 Cov.: 43 AF XY: 0.370 AC XY: 268012 AN XY: 724114

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: 0.560

Gnomad4 FIN exome AF: 0.406

Gnomad4 NFE exome AF: 0.355

Gnomad4 OTH exome AF: 0.361

GnomAD4 genome AF: 0.348 AC: 52753 AN: 151714 Hom.: 9415 Cov.: 32 AF XY: 0.351 AC XY: 26001 AN XY: 74090

Gnomad4 AFR AF: 0.331

Gnomad4 AMR AF: 0.278

Gnomad4 ASJ AF: 0.393

Gnomad4 EAS AF: 0.244

Gnomad4 SAS AF: 0.543

Gnomad4 FIN AF: 0.398

Gnomad4 NFE AF: 0.360

Gnomad4 OTH AF: 0.313

Alfa AF: 0.358 Hom.: 5425

Bravo AF: 0.330

TwinsUK AF: 0.351 AC: 1303

ALSPAC AF: 0.357 AC: 1374

ESP6500AA AF: 0.329 AC: 1450

ESP6500EA AF: 0.355 AC: 3054

ExAC AF: 0.359 AC: 43559

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_addAF	Benign	-0.29	T
BayesDel_noAF	Uncertain	-0.050
Cadd	Benign	12
Dann	Benign	0.97
Eigen	Uncertain	0.28
Eigen_PC	Uncertain	0.34
FATHMM_MKL	Uncertain	0.77	D
LIST_S2	Benign	0.29	T
MetaRNN	Benign	0.00022	T
MetaSVM	Benign	-1.0	T
MutationTaster	Benign	0.95	P;P;P
PROVEAN	Benign	-0.13	N
REVEL	Benign	0.090
Sift	Pathogenic	0.0	D
Vest4		0.057
ClinPred		0.048	T
GERP RS		5.1

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: rs12610234; hg19: chr19-35616316; COSMIC: COSV59532557; COSMIC: COSV59532557;