Genetic Variant LINGO4:p.Thr444Ser (chr1-151801375-T-A) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_001004432.4(LINGO4):c.1330A>T(p.Thr444Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0371 in 1,613,770 control chromosomes in the GnomAD database, including 7,318 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.058 ( 821 hom., cov: 33)

Exomes 𝑓: 0.035 ( 6497 hom. )

Consequence

LINGO4
NM_001004432.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.207

Publications

11 publications found

Variant links:

Genes affected

LINGO4 (HGNC:31814): (leucine rich repeat and Ig domain containing 4) Predicted to act upstream of or within positive regulation of synapse assembly. Predicted to be integral component of membrane. Predicted to be active in extracellular matrix and extracellular space. [provided by Alliance of Genome Resources, Apr 2022]

LINGO4 links:

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0012541711).

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.35 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LINGO4	NM_001004432.4 link	c.1330A>T	p.Thr444Ser	missense_variant	Exon 2 of 2	ENST00000368820.4	NP_001004432.1	Q6UY18

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LINGO4	ENST00000368820.4 link	c.1330A>T	p.Thr444Ser	missense_variant	Exon 2 of 2	1	NM_001004432.4	ENSP00000357810.4		Q6UY18

Frequencies

GnomAD3 genomes

AF:

0.0580

AC:

8824

AN:

152078

Hom.:

823

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0885

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.116

Gnomad ASJ

AF:

0.00259

Gnomad EAS

AF:

0.364

Gnomad SAS

AF:

0.242

Gnomad FIN

AF:

0.000283

Gnomad MID

AF:

0.0478

Gnomad NFE

AF:

0.00281

Gnomad OTH

AF:

0.0574

GnomAD2 exomes

AF:

0.0988

AC:

24825

AN:

251290

AF XY:

0.0954

show subpopulations

Gnomad AFR exome

AF:

0.0893

Gnomad AMR exome

AF:

0.246

Gnomad ASJ exome

AF:

0.00159

Gnomad EAS exome

AF:

0.391

Gnomad FIN exome

AF:

0.000463

Gnomad NFE exome

AF:

0.00272

Gnomad OTH exome

AF:

0.0576

GnomAD4 exome

AF:

0.0349

AC:

51010

AN:

1461574

Hom.:

6497

Cov.:

AF XY:

0.0389

AC XY:

28302

AN XY:

727038

show subpopulations

African (AFR)

AF:

0.0919

AC:

3077

AN:

33470

American (AMR)

AF:

0.233

AC:

10402

AN:

44716

Ashkenazi Jewish (ASJ)

AF:

0.00191

AC:

AN:

26136

East Asian (EAS)

AF:

0.334

AC:

13245

AN:

39680

South Asian (SAS)

AF:

0.222

AC:

19112

AN:

86248

European-Finnish (FIN)

AF:

0.000375

AC:

AN:

53384

Middle Eastern (MID)

AF:

0.0286

AC:

165

AN:

5768

European-Non Finnish (NFE)

AF:

0.00197

AC:

2193

AN:

1111804

Other (OTH)

AF:

0.0455

AC:

2746

AN:

60368

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.476

Heterozygous variant carriers

2820

5639

8459

11278

14098

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

704

1408

2112

2816

3520

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0580

AC:

8820

AN:

152196

Hom.:

821

Cov.:

AF XY:

0.0639

AC XY:

4756

AN XY:

74430

show subpopulations

African (AFR)

AF:

0.0886

AC:

3679

AN:

41546

American (AMR)

AF:

0.116

AC:

1767

AN:

15288

Ashkenazi Jewish (ASJ)

AF:

0.00259

AC:

AN:

3470

East Asian (EAS)

AF:

0.364

AC:

1875

AN:

5156

South Asian (SAS)

AF:

0.241

AC:

1163

AN:

4826

European-Finnish (FIN)

AF:

0.000283

AC:

AN:

10612

Middle Eastern (MID)

AF:

0.0479

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.00281

AC:

191

AN:

67982

Other (OTH)

AF:

0.0563

AC:

119

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

391

782

1173

1564

1955

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

114

228

342

456

570

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0192

Hom.:

238

Bravo

AF:

0.0705

TwinsUK

AF:

0.00162

AC:

ALSPAC

AF:

0.00441

AC:

ESP6500AA

AF:

0.0849

AC:

374

ESP6500EA

AF:

0.00256

AC:

ExAC

AF:

0.0947

AC:

11494

Asia WGS

AF:

0.227

AC:

790

AN:

3478

EpiCase

AF:

0.00262

EpiControl

AF:

0.00314

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.088

BayesDel_addAF

Benign

-0.68

BayesDel_noAF

Benign

-0.61

CADD

Benign

(source)

DANN

Benign

0.84

DEOGEN2

Benign

0.089

Eigen

Benign

-0.41

Eigen_PC

Benign

-0.24

FATHMM_MKL

Benign

0.27

LIST_S2

Benign

0.46

MetaRNN

Benign

0.0013

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.68

PhyloP100

0.21

PrimateAI

Benign

0.41

PROVEAN

Benign

0.020

REVEL

Benign

0.10

Sift

Benign

0.71

Sift4G

Benign

0.46

Polyphen

0.083

Vest4

0.042

MutPred

0.42

Gain of disorder (P = 0.0319);

MPC

0.13

ClinPred

0.010

GERP RS

5.5

Varity_R

0.049

gMVP

0.18

Mutation Taster

=96/4

polymorphism (auto)

(source)

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over