rs12978414

Variant names:

• chr19-35125658-C-G
• rs12978414
• ENST00000587780.5:c.*510G>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The ENST00000587780.5(LGI4):​c.*510G>C variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.358 in 736,320 control chromosomes in the GnomAD database, including 49,753 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.35 (9584 hom., cov: 32)
  • Exomes 𝑓: 0.36 (40169 hom.)
• Consequence: LGI4 ENST00000587780.5 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.0300
• Publications: 7 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: Labcorp Genetics (formerly Invitae), G2P
• hypomyelination neuropathy-arthrogryposis syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BP6: Variant 19-35125658-C-G is Benign according to our data. Variant chr19-35125658-C-G is described in ClinVar as Benign. ClinVar VariationId is 1294811.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.527 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LGI4	NM_139284.3	MANE Select	c.1300-151G>C		intron	N/A	NP_644813.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LGI4	ENST00000587780.5	TSL:1	c.*510G>C		3_prime_UTR	Exon 6 of 6	ENSP00000467044.2
	LGI4	ENST00000310123.8	TSL:1 MANE Select	c.1300-151G>C		intron	N/A	ENSP00000312273.3
	LGI4	ENST00000493050.5	TSL:1	n.1359-151G>C		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.349 AC: 53050 AN: 151878 Hom.: 9584 Cov.: 32

Gnomad AFR AF: 0.332

Gnomad AMI AF: 0.281

Gnomad AMR AF: 0.278

Gnomad ASJ AF: 0.393

Gnomad EAS AF: 0.246

Gnomad SAS AF: 0.546

Gnomad FIN AF: 0.402

Gnomad MID AF: 0.386

Gnomad NFE AF: 0.361

Gnomad OTH AF: 0.313

GnomAD4 exome AF: 0.360 AC: 210174 AN: 584324 Hom.: 40169 Cov.: 7 AF XY: 0.372 AC XY: 115822 AN XY: 311500

African (AFR) AF: 0.318 AC: 5142 AN: 16166

American (AMR) AF: 0.244 AC: 8055 AN: 32986

Ashkenazi Jewish (ASJ) AF: 0.373 AC: 7038 AN: 18876

East Asian (EAS) AF: 0.236 AC: 7594 AN: 32134

South Asian (SAS) AF: 0.547 AC: 32265 AN: 59028

European-Finnish (FIN) AF: 0.399 AC: 13465 AN: 33750

Middle Eastern (MID) AF: 0.373 AC: 1512 AN: 4052

European-Non Finnish (NFE) AF: 0.349 AC: 124170 AN: 355790

Other (OTH) AF: 0.347 AC: 10933 AN: 31542

GnomAD4 genome AF: 0.349 AC: 53079 AN: 151996 Hom.: 9584 Cov.: 32 AF XY: 0.353 AC XY: 26218 AN XY: 74290

African (AFR) AF: 0.332 AC: 13750 AN: 41436

American (AMR) AF: 0.278 AC: 4248 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.393 AC: 1363 AN: 3466

East Asian (EAS) AF: 0.246 AC: 1270 AN: 5164

South Asian (SAS) AF: 0.545 AC: 2628 AN: 4824

European-Finnish (FIN) AF: 0.402 AC: 4248 AN: 10562

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

European-Non Finnish (NFE) AF: 0.361 AC: 24536 AN: 67946

Other (OTH) AF: 0.314 AC: 664 AN: 2112

Alfa AF: 0.376 Hom.: 1373

Bravo AF: 0.330

Asia WGS AF: 0.387 AC: 1348 AN: 3478

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	-0.90
CADD	Benign	1.8
DANN	Benign	0.44
PhyloP100		-0.030
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs12978414; hg19: chr19-35616562; COSMIC: COSV59533978; COSMIC: COSV59533978;