rs17010021

Variant names:

Variant summary

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

The NM_032603.5(LOXL3):c.1843A>T(p.Ile615Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0547 in 1,614,118 control chromosomes in the GnomAD database, including 5,524 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I615T) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.055 ( 538 hom., cov: 33)

Exomes 𝑓: 0.055 ( 4986 hom. )

Consequence

LOXL3
NM_032603.5 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: 1.44

Publications

32 publications found

Variant links:

Genes affected

LOXL3 (HGNC:13869): (lysyl oxidase like 3) This gene encodes a lysyl oxidase, which likely functions as an amine oxidase and plays a role in the formation of crosslinks in collagens and elastin. Deletion of the related gene in mouse causes neonatal mortality with cleft palate, spine deformity, and defects in collagen organization. A mutation in this gene was found in a family with Stickler syndrome. [provided by RefSeq, Sep 2016]

LOXL3 Gene-Disease associations (from GenCC):

myopia 28, autosomal recessive
Inheritance: AR, Unknown Classification: STRONG, LIMITED Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)
Stickler syndrome
Inheritance: AR Classification: MODERATE, LIMITED Submitted by: Ambry Genetics, Genomics England PanelApp
autosomal recessive Stickler syndrome
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

LOXL3 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 (MetaRNN=0.0029302537).

BP6

Variant 2-74534412-T-A is Benign according to our data. Variant chr2-74534412-T-A is described in ClinVar as Benign. ClinVar VariationId is 262091.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.326 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LOXL3	NM_032603.5 link	c.1843A>T	p.Ile615Phe	missense_variant	Exon 11 of 14	ENST00000264094.8	NP_115992.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LOXL3	ENST00000264094.8 link	c.1843A>T	p.Ile615Phe	missense_variant	Exon 11 of 14	1	NM_032603.5	ENSP00000264094.3

Frequencies

GnomAD3 genomes

AF:

0.0545

AC:

8299

AN:

152164

Hom.:

538

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0274

Gnomad AMI

AF:

0.0230

Gnomad AMR

AF:

0.0916

Gnomad ASJ

AF:

0.0441

Gnomad EAS

AF:

0.340

Gnomad SAS

AF:

0.138

Gnomad FIN

AF:

0.0467

Gnomad MID

AF:

0.0253

Gnomad NFE

AF:

0.0373

Gnomad OTH

AF:

0.0564

GnomAD2 exomes

AF:

0.0825

AC:

20741

AN:

251482

AF XY:

0.0821

show subpopulations

Gnomad AFR exome

AF:

0.0274

Gnomad AMR exome

AF:

0.109

Gnomad ASJ exome

AF:

0.0347

Gnomad EAS exome

AF:

0.350

Gnomad FIN exome

AF:

0.0467

Gnomad NFE exome

AF:

0.0388

Gnomad OTH exome

AF:

0.0697

GnomAD4 exome

AF:

0.0547

AC:

80007

AN:

1461836

Hom.:

4986

Cov.:

AF XY:

0.0562

AC XY:

40891

AN XY:

727218

show subpopulations

African (AFR)

AF:

0.0231

AC:

773

AN:

33480

American (AMR)

AF:

0.107

AC:

4780

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.0359

AC:

938

AN:

26136

East Asian (EAS)

AF:

0.376

AC:

14934

AN:

39696

South Asian (SAS)

AF:

0.122

AC:

10527

AN:

86254

European-Finnish (FIN)

AF:

0.0464

AC:

2480

AN:

53420

Middle Eastern (MID)

AF:

0.0265

AC:

153

AN:

5768

European-Non Finnish (NFE)

AF:

0.0376

AC:

41782

AN:

1111964

Other (OTH)

AF:

0.0603

AC:

3640

AN:

60394

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.479

Heterozygous variant carriers

4430

8861

13291

17722

22152

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

1854

3708

5562

7416

9270

<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:

0.0545

AC:

8301

AN:

152282

Hom.:

538

Cov.:

AF XY:

0.0584

AC XY:

4346

AN XY:

74470

show subpopulations

African (AFR)

AF:

0.0274

AC:

1138

AN:

41556

American (AMR)

AF:

0.0917

AC:

1402

AN:

15296

Ashkenazi Jewish (ASJ)

AF:

0.0441

AC:

153

AN:

3470

East Asian (EAS)

AF:

0.339

AC:

1755

AN:

5174

South Asian (SAS)

AF:

0.138

AC:

667

AN:

4830

European-Finnish (FIN)

AF:

0.0467

AC:

496

AN:

10616

Middle Eastern (MID)

AF:

0.0238

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0373

AC:

2540

AN:

68020

Other (OTH)

AF:

0.0577

AC:

122

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

371

742

1112

1483

1854

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

196

294

392

490

<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:

0.0382

Hom.:

Bravo

AF:

0.0540

TwinsUK

AF:

0.0429

AC:

159

ALSPAC

AF:

0.0358

AC:

138

ESP6500AA

AF:

0.0286

AC:

126

ESP6500EA

AF:

0.0359

AC:

309

ExAC

AF:

0.0803

AC:

9748

Asia WGS

AF:

0.222

AC:

771

AN:

3478

EpiCase

AF:

0.0350

EpiControl

AF:

0.0359

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Oct 16, 2019

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is associated with the following publications: (PMID: 29802726) -

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

not specified

Benign:1

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.76

BayesDel_addAF

Benign

-0.50

BayesDel_noAF

Benign

-0.34

CADD

Uncertain

(source)

DANN

Uncertain

0.98

DEOGEN2

Benign

0.15

T;.;T;.

Eigen

Uncertain

0.32

Eigen_PC

Uncertain

0.30

FATHMM_MKL

Uncertain

0.94

LIST_S2

Uncertain

0.96

D;D;D;D

MetaRNN

Benign

0.0029

T;T;T;T

MetaSVM

Benign

-0.99

MutationAssessor

Benign

1.4

L;.;.;.

PhyloP100

1.4

PrimateAI

Uncertain

0.63

PROVEAN

Uncertain

-3.3

D;D;D;D

REVEL

Benign

0.14

Sift

Uncertain

0.0020

D;D;D;D

Sift4G

Uncertain

0.0070

D;D;D;D

Polyphen

0.92

P;.;D;D

Vest4

0.77

MPC

1.5

ClinPred

0.017

GERP RS

3.7

Varity_R

0.62

gMVP

0.79

Mutation Taster

=75/25

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

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over