Genetic Variant LOXL4:p.Asp405Ala (chr10-98257696-T-G) – ACMG Classification: Benign (-12 pts)

Variant summary

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

The NM_032211.7(LOXL4):c.1214A>C(p.Asp405Ala) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.348 in 1,613,840 control chromosomes in the GnomAD database, including 103,485 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.30 ( 8234 hom., cov: 33)

Exomes 𝑓: 0.35 ( 95251 hom. )

Consequence

LOXL4
NM_032211.7 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 8.02

Publications

54 publications found

Variant links:

Genes affected

LOXL4 (HGNC:17171): (lysyl oxidase like 4) This gene encodes a member of the lysyl oxidase gene family. The prototypic member of the family is essential to the biogenesis of connective tissue, encoding an extracellular copper-dependent amine oxidase that catalyses the first step in the formation of crosslinks in collagens and elastin. A highly conserved amino acid sequence at the C-terminus end appears to be sufficient for amine oxidase activity, suggesting that each family member may retain this function. The N-terminus is poorly conserved and may impart additional roles in developmental regulation, senescence, tumor suppression, cell growth control, and chemotaxis to each member of the family. [provided by RefSeq, Jul 2008]

LOXL4 Gene-Disease associations (from GenCC):

skeletal dysplasia
Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics

LOXL4 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

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

BP4

Computational evidence support a benign effect (MetaRNN=9.586215E-4).

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.55 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LOXL4	NM_032211.7 link	c.1214A>C	p.Asp405Ala	missense_variant	Exon 8 of 15	ENST00000260702.4	NP_115587.6	Q96JB6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LOXL4	ENST00000260702.4 link	c.1214A>C	p.Asp405Ala	missense_variant	Exon 8 of 15	1	NM_032211.7	ENSP00000260702.3		Q96JB6

Frequencies

GnomAD3 genomes

AF:

0.299

AC:

45473

AN:

152016

Hom.:

8228

Cov.:

show subpopulations

Gnomad AFR

AF:

0.101

Gnomad AMI

AF:

0.292

Gnomad AMR

AF:

0.451

Gnomad ASJ

AF:

0.324

Gnomad EAS

AF:

0.567

Gnomad SAS

AF:

0.445

Gnomad FIN

AF:

0.356

Gnomad MID

AF:

0.297

Gnomad NFE

AF:

0.345

Gnomad OTH

AF:

0.308

GnomAD2 exomes

AF:

0.387

AC:

97135

AN:

251288

AF XY:

0.386

show subpopulations

Gnomad AFR exome

AF:

0.0963

Gnomad AMR exome

AF:

0.585

Gnomad ASJ exome

AF:

0.318

Gnomad EAS exome

AF:

0.569

Gnomad FIN exome

AF:

0.344

Gnomad NFE exome

AF:

0.340

Gnomad OTH exome

AF:

0.369

GnomAD4 exome

AF:

0.353

AC:

515596

AN:

1461706

Hom.:

95251

Cov.:

AF XY:

0.355

AC XY:

257977

AN XY:

727176

show subpopulations

African (AFR)

AF:

0.0892

AC:

2985

AN:

33478

American (AMR)

AF:

0.571

AC:

25508

AN:

44704

Ashkenazi Jewish (ASJ)

AF:

0.323

AC:

8446

AN:

26126

East Asian (EAS)

AF:

0.527

AC:

20914

AN:

39696

South Asian (SAS)

AF:

0.441

AC:

37997

AN:

86248

European-Finnish (FIN)

AF:

0.345

AC:

18399

AN:

53384

Middle Eastern (MID)

AF:

0.352

AC:

2032

AN:

5766

European-Non Finnish (NFE)

AF:

0.340

AC:

378013

AN:

1111922

Other (OTH)

AF:

0.353

AC:

21302

AN:

60382

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.487

Heterozygous variant carriers

18531

37063

55594

74126

92657

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

12230

24460

36690

48920

61150

<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:

0.299

AC:

45484

AN:

152134

Hom.:

8234

Cov.:

AF XY:

0.305

AC XY:

22699

AN XY:

74356

show subpopulations

African (AFR)

AF:

0.101

AC:

4191

AN:

41540

American (AMR)

AF:

0.451

AC:

6901

AN:

15294

Ashkenazi Jewish (ASJ)

AF:

0.324

AC:

1126

AN:

3470

East Asian (EAS)

AF:

0.568

AC:

2921

AN:

5146

South Asian (SAS)

AF:

0.446

AC:

2150

AN:

4818

European-Finnish (FIN)

AF:

0.356

AC:

3769

AN:

10580

Middle Eastern (MID)

AF:

0.299

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.345

AC:

23426

AN:

67966

Other (OTH)

AF:

0.305

AC:

646

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

1555

3110

4666

6221

7776

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

474

948

1422

1896

2370

<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:

0.334

Hom.:

40030

Bravo

AF:

0.297

TwinsUK

AF:

0.331

AC:

1229

ALSPAC

AF:

0.348

AC:

1343

ESP6500AA

AF:

0.105

AC:

462

ESP6500EA

AF:

0.327

AC:

2808

ExAC

AF:

0.373

AC:

45329

Asia WGS

AF:

0.478

AC:

1663

AN:

3478

EpiCase

AF:

0.338

EpiControl

AF:

0.335

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.88

BayesDel_addAF

Benign

-0.42

BayesDel_noAF

Benign

-0.23

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.27

Eigen

Pathogenic

0.78

Eigen_PC

Pathogenic

0.74

FATHMM_MKL

Uncertain

0.96

LIST_S2

Pathogenic

1.0

MetaRNN

Benign

0.00096

MetaSVM

Benign

-0.87

MutationAssessor

Uncertain

2.9

PhyloP100

8.0

PrimateAI

Uncertain

0.57

PROVEAN

Pathogenic

-6.7

REVEL

Uncertain

0.40

Sift

Pathogenic

0.0

Sift4G

Benign

0.15

Polyphen

1.0

Vest4

0.33

MPC

0.60

ClinPred

0.044

GERP RS

5.5

Varity_R

0.96

gMVP

0.93

Mutation Taster

=71/29

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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