NM_139284.3:c.1395G>A

Variant names:

• chr19-35125412-C-T
• rs12610234
• NM_139284.3:c.1395G>A

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.1395G>A​(p.Gln465Gln) 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:3
• Conservation: PhyloP100: 2.30
• Publications: 16 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 (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 VariationId 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.

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.1395G>A	p.Gln465Gln	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.1395G>A	p.Gln465Gln	synonymous	Exon 9 of 9	ENSP00000312273.3	Q8N135-1
	LGI4	ENST00000587780.5	TSL:1	c.*756G>A		3_prime_UTR	Exon 6 of 6	ENSP00000467044.2	K7ENQ0
	LGI4	ENST00000493050.5	TSL:1	n.1454G>A		non_coding_transcript_exon	Exon 10 of 10

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

GnomAD2 exomes AF: 0.364 AC: 87702 AN: 241074 AF XY: 0.378

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 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

African (AFR) AF: 0.323 AC: 10809 AN: 33440

American (AMR) AF: 0.258 AC: 11321 AN: 43800

Ashkenazi Jewish (ASJ) AF: 0.390 AC: 10141 AN: 26012

East Asian (EAS) AF: 0.238 AC: 9398 AN: 39510

South Asian (SAS) AF: 0.560 AC: 48022 AN: 85820

European-Finnish (FIN) AF: 0.406 AC: 21441 AN: 52834

Middle Eastern (MID) AF: 0.379 AC: 2178 AN: 5748

European-Non Finnish (NFE) AF: 0.355 AC: 393643 AN: 1109336

Other (OTH) AF: 0.361 AC: 21691 AN: 60164

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

African (AFR) AF: 0.331 AC: 13685 AN: 41380

American (AMR) AF: 0.278 AC: 4242 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.393 AC: 1361 AN: 3462

East Asian (EAS) AF: 0.244 AC: 1256 AN: 5152

South Asian (SAS) AF: 0.543 AC: 2610 AN: 4806

European-Finnish (FIN) AF: 0.398 AC: 4183 AN: 10516

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

European-Non Finnish (NFE) AF: 0.360 AC: 24389 AN: 67808

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

Alfa AF: 0.356 Hom.: 6990

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

ClinVar submissions

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
AlphaMissense	Benign	0.25
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
PhyloP100		2.3
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
Mutation Taster		=87/13	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: rs12610234; hg19: chr19-35616316; COSMIC: COSV59532557; COSMIC: COSV59532557;