Genetic Variant NM_032603.5:c.1124G>A (chr2-74536120-C-T) – ACMG Classification: Benign (-20 pts)

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_032603.5(LOXL3):c.1124G>A(p.Arg375His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0189 in 1,613,852 control chromosomes in the GnomAD database, including 373 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict 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. R375C) has been classified as Benign.

Frequency

Genomes: 𝑓 0.015 ( 24 hom., cov: 32)

Exomes 𝑓: 0.019 ( 349 hom. )

Consequence

LOXL3
NM_032603.5 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: 0.937

Publications

9 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: Genomics England PanelApp, Ambry Genetics
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=0.014687121).

BP6

Variant 2-74536120-C-T is Benign according to our data. Variant chr2-74536120-C-T is described in ClinVar as Benign. ClinVar VariationId is 262090.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0146 (2221/152238) while in subpopulation NFE AF = 0.0232 (1577/67998). AF 95% confidence interval is 0.0222. There are 24 homozygotes in GnomAd4. There are 1026 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 24 AR,Unknown gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_032603.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
LOXL3	NM_032603.5	MANE Select	c.1124G>A	p.Arg375His	missense	Exon 7 of 14	NP_115992.1	P58215-1
LOXL3	NM_001289164.3		c.689G>A	p.Arg230His	missense	Exon 5 of 12	NP_001276093.1	P58215-3
LOXL3	NM_001289165.2		c.41G>A	p.Arg14His	missense	Exon 3 of 10	NP_001276094.1	P58215-2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
LOXL3	ENST00000264094.8	TSL:1 MANE Select	c.1124G>A	p.Arg375His	missense	Exon 7 of 14	ENSP00000264094.3	P58215-1
LOXL3	ENST00000946469.1		c.1124G>A	p.Arg375His	missense	Exon 6 of 13	ENSP00000616528.1
LOXL3	ENST00000853956.1		c.1124G>A	p.Arg375His	missense	Exon 7 of 14	ENSP00000524015.1

Frequencies

GnomAD3 genomes

AF:

0.0146

AC:

2224

AN:

152120

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00512

Gnomad AMI

AF:

0.00877

Gnomad AMR

AF:

0.0139

Gnomad ASJ

AF:

0.00548

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00352

Gnomad FIN

AF:

0.0119

Gnomad MID

AF:

0.0158

Gnomad NFE

AF:

0.0232

Gnomad OTH

AF:

0.0220

GnomAD2 exomes

AF:

0.0147

AC:

3687

AN:

251176

AF XY:

0.0153

show subpopulations

Gnomad AFR exome

AF:

0.00449

Gnomad AMR exome

AF:

0.0118

Gnomad ASJ exome

AF:

0.00864

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0123

Gnomad NFE exome

AF:

0.0228

Gnomad OTH exome

AF:

0.0171

GnomAD4 exome

AF:

0.0194

AC:

28340

AN:

1461614

Hom.:

349

Cov.:

AF XY:

0.0192

AC XY:

13969

AN XY:

727128

show subpopulations

African (AFR)

AF:

0.00343

AC:

115

AN:

33480

American (AMR)

AF:

0.0115

AC:

515

AN:

44716

Ashkenazi Jewish (ASJ)

AF:

0.00731

AC:

191

AN:

26130

East Asian (EAS)

AF:

0.0000252

AC:

AN:

39700

South Asian (SAS)

AF:

0.00541

AC:

467

AN:

86258

European-Finnish (FIN)

AF:

0.0129

AC:

684

AN:

53192

Middle Eastern (MID)

AF:

0.0123

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.0228

AC:

25319

AN:

1111980

Other (OTH)

AF:

0.0162

AC:

977

AN:

60390

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.473

Heterozygous variant carriers

1612

3224

4837

6449

8061

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

928

1856

2784

3712

4640

<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:

0.0146

AC:

2221

AN:

152238

Hom.:

Cov.:

AF XY:

0.0138

AC XY:

1026

AN XY:

74416

show subpopulations

African (AFR)

AF:

0.00510

AC:

212

AN:

41528

American (AMR)

AF:

0.0139

AC:

212

AN:

15300

Ashkenazi Jewish (ASJ)

AF:

0.00548

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5188

South Asian (SAS)

AF:

0.00353

AC:

AN:

4822

European-Finnish (FIN)

AF:

0.0119

AC:

126

AN:

10614

Middle Eastern (MID)

AF:

0.0136

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0232

AC:

1577

AN:

67998

Other (OTH)

AF:

0.0218

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

116

232

347

463

579

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

120

<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:

0.0199

Hom.:

125

Bravo

AF:

0.0141

TwinsUK

AF:

0.0232

AC:

ALSPAC

AF:

0.0262

AC:

101

ESP6500AA

AF:

0.00658

AC:

ESP6500EA

AF:

0.0231

AC:

199

ExAC

AF:

0.0149

AC:

1803

Asia WGS

AF:

0.00346

AC:

AN:

3478

EpiCase

AF:

0.0219

EpiControl

AF:

0.0252

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (2)

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.065

BayesDel_addAF

Benign

-0.48

BayesDel_noAF

Benign

-0.45

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.031

Eigen

Benign

0.079

Eigen_PC

Benign

0.094

FATHMM_MKL

Benign

0.41

LIST_S2

Benign

0.85

MetaRNN

Benign

0.015

MetaSVM

Benign

-0.99

MutationAssessor

Benign

0.98

PhyloP100

0.94

PrimateAI

Benign

0.41

PROVEAN

Benign

-1.7

REVEL

Benign

0.068

Sift

Benign

0.067

Sift4G

Benign

0.47

Polyphen

0.96

Vest4

0.082

MPC

1.0

ClinPred

0.014

GERP RS

4.2

Varity_R

0.052

gMVP

0.46

Mutation Taster

=98/2

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.060

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over