Genetic Variant LOXL1:c.*432A>G (chr15-73952269-A-G) – ACMG Classification: Benign (-14 pts)

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_StrongBP6_ModerateBA1

The NM_005576.4(LOXL1):c.*432A>G variant causes a downstream gene change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.22 in 161,388 control chromosomes in the GnomAD database, including 4,095 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

Frequency

Genomes: 𝑓 0.22 ( 3860 hom., cov: 33)

Exomes 𝑓: 0.22 ( 235 hom. )

Consequence

LOXL1
NM_005576.4 downstream_gene

Scores

Clinical Significance

Benign criteria provided, single submitter B:1

Conservation

PhyloP100: 0.308

Publications

10 publications found

Variant links:

Genes affected

LOXL1 (HGNC:6665): (lysyl oxidase like 1) This gene encodes a member of the lysyl oxidase family of proteins. The prototypic member of the family is essential to the biogenesis of connective tissue, encoding an extracellular copper-dependent amine oxidase that catalyzes the first step in the formation of crosslinks in collagen and elastin. The encoded preproprotein is proteolytically processed to generate the mature enzyme. 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. Mutations in this gene are associated with exfoliation syndrome. [provided by RefSeq, Jan 2016]

LOXL1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -14 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.9).

BP6

Variant 15-73952269-A-G is Benign according to our data. Variant chr15-73952269-A-G is described in ClinVar as Benign. ClinVar VariationId is 1266506.Status of the report is criteria_provided_single_submitter, 1 stars.

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.371 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LOXL1	NM_005576.4 link	c.*432A>G		downstream_gene_variant		ENST00000261921.8	NP_005567.2
LOXL1	XM_017022179.2 link	c.*432A>G		downstream_gene_variant			XP_016877668.1

Ensembl

Gene	Transcript	HGVSc	Effect	TSL	MANE	Protein
LOXL1	ENST00000261921.8 link	c.*432A>G	downstream_gene_variant	1	NM_005576.4	ENSP00000261921.7
LOXL1	ENST00000562548.1 link	n.*132A>G	downstream_gene_variant	2
LOXL1	ENST00000567675.1 link	n.*133A>G	downstream_gene_variant	3

Frequencies

GnomAD3 genomes

AF:

0.220

AC:

33425

AN:

151978

Hom.:

3847

Cov.:

show subpopulations

Gnomad AFR

AF:

0.232

Gnomad AMI

AF:

0.211

Gnomad AMR

AF:

0.171

Gnomad ASJ

AF:

0.248

Gnomad EAS

AF:

0.290

Gnomad SAS

AF:

0.386

Gnomad FIN

AF:

0.185

Gnomad MID

AF:

0.263

Gnomad NFE

AF:

0.210

Gnomad OTH

AF:

0.239

GnomAD4 exome

AF:

0.216

AC:

2003

AN:

9292

Hom.:

235

AF XY:

0.206

AC XY:

985

AN XY:

4772

show subpopulations

African (AFR)

AF:

0.226

AC:

AN:

438

American (AMR)

AF:

0.167

AC:

AN:

246

Ashkenazi Jewish (ASJ)

AF:

0.198

AC:

AN:

384

East Asian (EAS)

AF:

0.314

AC:

164

AN:

522

South Asian (SAS)

AF:

0.412

AC:

AN:

European-Finnish (FIN)

AF:

0.185

AC:

AN:

352

Middle Eastern (MID)

AF:

0.293

AC:

AN:

European-Non Finnish (NFE)

AF:

0.206

AC:

1348

AN:

6540

Other (OTH)

AF:

0.238

AC:

160

AN:

672

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.508

Heterozygous variant carriers

155

233

310

388

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

100

<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:

0.220

AC:

33470

AN:

152096

Hom.:

3860

Cov.:

AF XY:

0.223

AC XY:

16561

AN XY:

74344

show subpopulations

African (AFR)

AF:

0.232

AC:

9633

AN:

41522

American (AMR)

AF:

0.171

AC:

2609

AN:

15298

Ashkenazi Jewish (ASJ)

AF:

0.248

AC:

859

AN:

3470

East Asian (EAS)

AF:

0.290

AC:

1491

AN:

5134

South Asian (SAS)

AF:

0.386

AC:

1863

AN:

4832

European-Finnish (FIN)

AF:

0.185

AC:

1958

AN:

10598

Middle Eastern (MID)

AF:

0.262

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.210

AC:

14270

AN:

67930

Other (OTH)

AF:

0.246

AC:

518

AN:

2106

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.506

Heterozygous variant carriers

1375

2749

4124

5498

6873

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

378

756

1134

1512

1890

<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:

0.214

Hom.:

6566

Bravo

AF:

0.217

Asia WGS

AF:

0.363

AC:

1263

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Benign:1

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: 30986821) -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.90

CADD

Benign

2.6

(source)

DANN

Benign

0.35

PhyloP100

0.31

Splicing

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