rs937087

Variant names:

• chr19-35126218-A-G
• rs937087
• ENST00000587780.5:c.1084T>C

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The ENST00000587780.5(LGI4):​c.1084T>C​(p.Leu362Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.359 in 1,580,818 control chromosomes in the GnomAD database, including 104,086 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.34 (9267 hom., cov: 31)
  • Exomes 𝑓: 0.36 (94819 hom.)
• Consequence: LGI4 ENST00000587780.5 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.153
• Publications: 10 publications found

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]

LGI4 Gene-Disease associations (from GenCC):

• arthrogryposis multiplex congenita 1, neurogenic, with myelin defect

  Inheritance: AR Classification: STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae)
• hypomyelination neuropathy-arthrogryposis syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• BP6: Variant 19-35126218-A-G is Benign according to our data. Variant chr19-35126218-A-G is described in ClinVar as Benign. ClinVar VariationId is 1266397.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.153 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.487 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000587780.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LGI4	NM_139284.3	MANE Select	c.1299+52T>C		intron	N/A	NP_644813.1	Q8N135-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LGI4	ENST00000587780.5	TSL:1	c.1084T>C	p.Leu362Leu	synonymous	Exon 6 of 6	ENSP00000467044.2	K7ENQ0
	LGI4	ENST00000310123.8	TSL:1 MANE Select	c.1299+52T>C		intron	N/A	ENSP00000312273.3	Q8N135-1
	LGI4	ENST00000493050.5	TSL:1	n.1358+52T>C		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.344 AC: 52234 AN: 151734 Hom.: 9270 Cov.: 31

Gnomad AFR AF: 0.320

Gnomad AMI AF: 0.281

Gnomad AMR AF: 0.278

Gnomad ASJ AF: 0.392

Gnomad EAS AF: 0.237

Gnomad SAS AF: 0.504

Gnomad FIN AF: 0.402

Gnomad MID AF: 0.386

Gnomad NFE AF: 0.361

Gnomad OTH AF: 0.309

GnomAD2 exomes AF: 0.357 AC: 76824 AN: 215126 AF XY: 0.370

Gnomad AFR exome AF: 0.315

Gnomad AMR exome AF: 0.257

Gnomad ASJ exome AF: 0.383

Gnomad EAS exome AF: 0.241

Gnomad FIN exome AF: 0.405

Gnomad NFE exome AF: 0.354

Gnomad OTH exome AF: 0.362

GnomAD4 exome AF: 0.360 AC: 514543 AN: 1428968 Hom.: 94819 Cov.: 29 AF XY: 0.366 AC XY: 259330 AN XY: 708038

African (AFR) AF: 0.311 AC: 10282 AN: 33068

American (AMR) AF: 0.257 AC: 10545 AN: 41080

Ashkenazi Jewish (ASJ) AF: 0.389 AC: 9876 AN: 25400

East Asian (EAS) AF: 0.230 AC: 8938 AN: 38894

South Asian (SAS) AF: 0.524 AC: 43259 AN: 82628

European-Finnish (FIN) AF: 0.405 AC: 20734 AN: 51162

Middle Eastern (MID) AF: 0.377 AC: 2156 AN: 5720

European-Non Finnish (NFE) AF: 0.355 AC: 387686 AN: 1091938

Other (OTH) AF: 0.357 AC: 21067 AN: 59078

GnomAD4 genome AF: 0.344 AC: 52253 AN: 151850 Hom.: 9267 Cov.: 31 AF XY: 0.347 AC XY: 25751 AN XY: 74218

African (AFR) AF: 0.320 AC: 13245 AN: 41404

American (AMR) AF: 0.277 AC: 4239 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.392 AC: 1358 AN: 3466

East Asian (EAS) AF: 0.237 AC: 1221 AN: 5152

South Asian (SAS) AF: 0.503 AC: 2422 AN: 4812

European-Finnish (FIN) AF: 0.402 AC: 4237 AN: 10546

Middle Eastern (MID) AF: 0.395 AC: 116 AN: 294

European-Non Finnish (NFE) AF: 0.361 AC: 24514 AN: 67882

Other (OTH) AF: 0.306 AC: 645 AN: 2106

Alfa AF: 0.364 Hom.: 2157

Bravo AF: 0.326

Asia WGS AF: 0.348 AC: 1211 AN: 3474

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	2.7
DANN	Benign	0.73
PhyloP100		-0.15
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs937087; hg19: chr19-35617122; COSMIC: COSV107381937; COSMIC: COSV107381937;