chr19-35125207-C-T

Variant names:

• chr19-35125207-C-T
• rs777456550
• NM_139284.3:c.1600G>A

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 1P and 1B. PP3 BS1_Supporting

The NM_139284.3(LGI4):​c.1600G>A​(p.Asp534Asn) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000378 in 1,374,688 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.000038 (0 hom.)
• Consequence: LGI4 NM_139284.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.50
• Publications: 0 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: Uncertain_significance. The variant received 0 ACMG points.

• PP3: MetaRNN computational evidence supports a deleterious effect, 0.769
• BS1: Variant frequency is greater than expected in population sas. GnomAdExome4 allele frequency = 0.0000378 (52/1374688) while in subpopulation SAS AF = 0.000312 (23/73772). AF 95% confidence interval is 0.000213. There are 0 homozygotes in GnomAdExome4. There are 30 alleles in the male GnomAdExome4 subpopulation. Median coverage is 36. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

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.1600G>A	p.Asp534Asn	missense	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.1600G>A	p.Asp534Asn	missense	Exon 9 of 9	ENSP00000312273.3	Q8N135-1
	LGI4	ENST00000587780.5	TSL:1	c.*961G>A		3_prime_UTR	Exon 6 of 6	ENSP00000467044.2	K7ENQ0
	LGI4	ENST00000493050.5	TSL:1	n.1659G>A		non_coding_transcript_exon	Exon 10 of 10

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.0000415 AC: 8 AN: 192994 AF XY: 0.0000585

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000123

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000218

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000378 AC: 52 AN: 1374688 Hom.: 0 Cov.: 36 AF XY: 0.0000445 AC XY: 30 AN XY: 673856

African (AFR) AF: 0.00 AC: 0 AN: 30700

American (AMR) AF: 0.00 AC: 0 AN: 32352

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 20894

East Asian (EAS) AF: 0.0000776 AC: 3 AN: 38672

South Asian (SAS) AF: 0.000312 AC: 23 AN: 73772

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 50222

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5358

European-Non Finnish (NFE) AF: 0.0000234 AC: 25 AN: 1066334

Other (OTH) AF: 0.0000177 AC: 1 AN: 56384

GnomAD4 genome Cov.: 33

Alfa AF: 0.0000870 Hom.: 0

Bravo AF: 0.00000756

ExAC AF: 0.0000578 AC: 7

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.29
BayesDel_addAF	Benign	-0.14	T
BayesDel_noAF	Benign	-0.16
CADD	Pathogenic	27
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.75	D
Eigen	Uncertain	0.62
Eigen_PC	Uncertain	0.55
FATHMM_MKL	Uncertain	0.84	D
LIST_S2	Benign	0.84	T
M_CAP	Uncertain	0.26	D
MetaRNN	Pathogenic	0.77	D
MetaSVM	Uncertain	0.31	D
MutationAssessor	Uncertain	2.6	M
PhyloP100		7.5
PrimateAI	Uncertain	0.68	T
PROVEAN	Uncertain	-4.3	D
REVEL	Uncertain	0.47
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.85
MutPred		0.38		Gain of relative solvent accessibility (P = 0.1259)
MVP		0.89
MPC		0.94
ClinPred		0.88	D
GERP RS		5.2
Varity_R		0.78
gMVP		0.85
Mutation Taster		=59/41	polymorphism

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: rs777456550; hg19: chr19-35616111;