NM_139284.3:c.1396C>T

Variant names:

• chr19-35125411-G-A
• rs12610146
• NM_139284.3:c.1396C>T

Variant summary

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

The NM_139284.3(LGI4):​c.1396C>T​(p.Leu466Leu) 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:3
• Conservation: PhyloP100: 3.12
• Publications: 15 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]

FXYD3 (HGNC:4027): (FXYD domain containing ion transport regulator 3) This gene belongs to a small family of FXYD-domain containing regulators of Na+/K+ ATPases which share a 35-amino acid signature sequence domain, beginning with the sequence PFXYD, and containing 7 invariant and 6 highly conserved amino acids. This gene encodes a cell membrane protein that may regulate the function of ion-pumps and ion-channels. This gene may also play a role in tumor progression. Alternative splicing results in multiple transcript variants encoding distinct isoforms.[provided by RefSeq, Oct 2008]

ACMG classification

Our verdict: Benign. The variant received -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 VariationId 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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_139284.3. 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.1396C>T	p.Leu466Leu	synonymous	Exon 9 of 9	NP_644813.1	Q8N135-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LGI4	ENST00000310123.8	TSL:1 MANE Select	c.1396C>T	p.Leu466Leu	synonymous	Exon 9 of 9	ENSP00000312273.3	Q8N135-1
	LGI4	ENST00000587780.5	TSL:1	c.*757C>T		3_prime_UTR	Exon 6 of 6	ENSP00000467044.2	K7ENQ0
	LGI4	ENST00000493050.5	TSL:1	n.1455C>T		non_coding_transcript_exon	Exon 10 of 10

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

GnomAD2 exomes AF: 0.363 AC: 87675 AN: 241300 AF XY: 0.377

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 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

African (AFR) AF: 0.323 AC: 10809 AN: 33444

American (AMR) AF: 0.258 AC: 11312 AN: 43816

Ashkenazi Jewish (ASJ) AF: 0.390 AC: 10145 AN: 26020

East Asian (EAS) AF: 0.238 AC: 9400 AN: 39530

South Asian (SAS) AF: 0.559 AC: 48023 AN: 85840

European-Finnish (FIN) AF: 0.406 AC: 21442 AN: 52862

Middle Eastern (MID) AF: 0.379 AC: 2178 AN: 5752

European-Non Finnish (NFE) AF: 0.355 AC: 393640 AN: 1109406

Other (OTH) AF: 0.360 AC: 21690 AN: 60174

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

African (AFR) AF: 0.330 AC: 13684 AN: 41404

American (AMR) AF: 0.277 AC: 4242 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.393 AC: 1361 AN: 3466

East Asian (EAS) AF: 0.244 AC: 1255 AN: 5152

South Asian (SAS) AF: 0.542 AC: 2608 AN: 4808

European-Finnish (FIN) AF: 0.398 AC: 4182 AN: 10514

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

European-Non Finnish (NFE) AF: 0.360 AC: 24386 AN: 67816

Other (OTH) AF: 0.313 AC: 660 AN: 2108

Alfa AF: 0.358 Hom.: 4630

Bravo AF: 0.330

Asia WGS AF: 0.387 AC: 1345 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	Arthrogryposis multiplex congenita 1, neurogenic, with myelin defect (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.55
CADD	Benign	7.6
DANN	Benign	0.94
PhyloP100		3.1
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: rs12610146; hg19: chr19-35616315; COSMIC: COSV59532541; COSMIC: COSV59532541;