8-22148657-C-T

Variant names:

• chr8-22148657-C-T
• rs149352514
• NM_139278.4:c.1150G>A

Variant summary

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

The NM_139278.4(LGI3):​c.1150G>A​(p.Gly384Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00272 in 1,614,014 control chromosomes in the GnomAD database, including 146 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0046 (17 hom., cov: 32)
  • Exomes 𝑓: 0.0025 (129 hom.)
• Consequence: LGI3 NM_139278.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 3.14
• Publications: 4 publications found

Genes affected

LGI3 (HGNC:18711): (leucine rich repeat LGI family member 3) Predicted to enable catalytic activity. Predicted to be involved in regulation of exocytosis. Predicted to be located in extracellular region. Predicted to be active in synaptic vesicle. [provided by Alliance of Genome Resources, Apr 2022]

LGI3 Gene-Disease associations (from GenCC):

• intellectual developmental disorder with muscle tone abnormalities and distal skeletal defects

  Inheritance: AR, Unknown Classification: LIMITED Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)

ACMG classification

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

• BP4: Computational evidence support a benign effect (MetaRNN=0.0016196668).
• BP6: Variant 8-22148657-C-T is Benign according to our data. Variant chr8-22148657-C-T is described in ClinVar as Benign. ClinVar VariationId is 770570.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAdExome4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.0735 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_139278.4. 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
	LGI3	NM_139278.4	MANE Select	c.1150G>A	p.Gly384Ser	missense	Exon 8 of 8	NP_644807.1	Q8N145-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LGI3	ENST00000306317.7	TSL:1 MANE Select	c.1150G>A	p.Gly384Ser	missense	Exon 8 of 8	ENSP00000302297.2	Q8N145-1
	LGI3	ENST00000424267.6	TSL:1	c.1078G>A	p.Gly360Ser	missense	Exon 7 of 7	ENSP00000399121.2	Q8N145-2
	LGI3	ENST00000520124.5	TSL:1	n.2593G>A		non_coding_transcript_exon	Exon 6 of 6

Frequencies

GnomAD3 genomes AF: 0.00460 AC: 700 AN: 152160 Hom.: 16 Cov.: 32

Gnomad AFR AF: 0.00181

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0388

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000206

Gnomad OTH AF: 0.00813

GnomAD2 exomes AF: 0.0111 AC: 2796 AN: 251116 AF XY: 0.00855

Gnomad AFR exome AF: 0.00142

Gnomad AMR exome AF: 0.0780

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000544

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000704

Gnomad OTH exome AF: 0.00963

GnomAD4 exome AF: 0.00252 AC: 3690 AN: 1461736 Hom.: 129 Cov.: 32 AF XY: 0.00220 AC XY: 1597 AN XY: 727168

African (AFR) AF: 0.000777 AC: 26 AN: 33480

American (AMR) AF: 0.0756 AC: 3381 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.000151 AC: 6 AN: 39700

South Asian (SAS) AF: 0.000429 AC: 37 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53280

Middle Eastern (MID) AF: 0.000173 AC: 1 AN: 5766

European-Non Finnish (NFE) AF: 0.0000585 AC: 65 AN: 1112002

Other (OTH) AF: 0.00288 AC: 174 AN: 60394

GnomAD4 genome AF: 0.00463 AC: 705 AN: 152278 Hom.: 17 Cov.: 32 AF XY: 0.00474 AC XY: 353 AN XY: 74476

African (AFR) AF: 0.00180 AC: 75 AN: 41560

American (AMR) AF: 0.0391 AC: 598 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5182

South Asian (SAS) AF: 0.00 AC: 0 AN: 4822

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10618

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000206 AC: 14 AN: 68010

Other (OTH) AF: 0.00804 AC: 17 AN: 2114

Alfa AF: 0.00143 Hom.: 13

Bravo AF: 0.00943

ESP6500AA AF: 0.00159 AC: 7

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.00852 AC: 1034

Asia WGS AF: 0.00144 AC: 5 AN: 3478

EpiCase AF: 0.00

EpiControl AF: 0.000119

ClinVar

ClinVar submissions

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
AlphaMissense	Benign	0.076
BayesDel_addAF	Benign	-0.38	T
BayesDel_noAF	Benign	-0.26
CADD	Benign	20
DANN	Uncertain	1.0
DEOGEN2	Benign	0.12	T
Eigen	Benign	-0.12
Eigen_PC	Benign	-0.13
FATHMM_MKL	Benign	0.36	N
LIST_S2	Uncertain	0.93	D
MetaRNN	Benign	0.0016	T
MetaSVM	Benign	-0.55	T
MutationAssessor	Benign	0.0	N
PhyloP100		3.1
PrimateAI	Benign	0.41	T
PROVEAN	Benign	1.4	N
REVEL	Benign	0.26
Sift	Uncertain	0.011	D
Sift4G	Uncertain	0.052	T
Polyphen		0.95	P
Vest4		0.18
MPC		0.33
ClinPred		0.034	T
GERP RS		5.1
Varity_R		0.092
gMVP		0.55
Mutation Taster		=98/2	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: rs149352514; hg19: chr8-22006170; COSMIC: COSV60444629; COSMIC: COSV60444629;