dbSNP rs12978414: LGI4:c.*510G>C (chr19-35125658-C-G) – ACMG Classification: Benign (-20 pts)

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

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

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: -0.0300

Publications

7 publications found

Variant links:

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

LGI4 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

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 id 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LGI4	NM_139284.3 link	c.1300-151G>C		intron_variant	Intron 8 of 8	ENST00000310123.8	NP_644813.1	Q8N135-1A5D6Y5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LGI4	ENST00000310123.8 link	c.1300-151G>C		intron_variant	Intron 8 of 8	1	NM_139284.3	ENSP00000312273.3		Q8N135-1

Frequencies

GnomAD3 genomes

AF:

0.349

AC:

53050

AN:

151878

Hom.:

9584

Cov.:

show subpopulations

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.:

AF XY:

0.372

AC XY:

115822

AN XY:

311500

show subpopulations

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

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.450

Heterozygous variant carriers

5364

10729

16093

21458

26822

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.349

AC:

53079

AN:

151996

Hom.:

9584

Cov.:

AF XY:

0.353

AC XY:

26218

AN XY:

74290

show subpopulations

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

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

1720

3440

5159

6879

8599

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.376

Hom.:

1373

Bravo

AF:

0.330

Asia WGS

AF:

0.387

AC:

1348

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

May 12, 2021

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.90

CADD

Benign

1.8

(source)

DANN

Benign

0.44

PhyloP100

-0.030

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

Publications

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rs12978414

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over