rs3825942

Positions:

• chr15-73927241-G-A
• chr15-73927241-G-C
• chr15-73927241-G-T

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_005576.4(LOXL1):​c.458G>A​(p.Gly153Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.171 in 1,597,506 control chromosomes in the GnomAD database, including 25,880 homozygotes. In-silico tool predicts a benign outcome for this variant. 11/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.22 (4501 hom., cov: 33)
  • Exomes 𝑓: 0.17 (21379 hom.)
• Consequence: LOXL1 NM_005576.4 missense
• Clinical Significance: Benign criteria provided, single submitter B:1 O:1
• Conservation: PhyloP100: 0.949

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-AS1 (HGNC:44169): (LOXL1 antisense RNA 1)

ACMG classification

Verdict is Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0014670193).
• BP6: Variant 15-73927241-G-A is Benign according to our data. Variant chr15-73927241-G-A is described in ClinVar as [Benign]. Clinvar id is 14361.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.374 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LOXL1	NM_005576.4	c.458G>A	p.Gly153Asp	missense_variant	1/7	ENST00000261921.8
LOXL1-AS1	NR_040069.1	n.184+824C>T		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LOXL1	ENST00000261921.8	c.458G>A	p.Gly153Asp	missense_variant	1/7	1	NM_005576.4	P1
LOXL1-AS1	ENST00000685373.1	n.198+536C>T		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes AF: 0.222 AC: 33661 AN: 151938 Hom.: 4490 Cov.: 33

Gnomad AFR AF: 0.379

Gnomad AMI AF: 0.209

Gnomad AMR AF: 0.153

Gnomad ASJ AF: 0.174

Gnomad EAS AF: 0.123

Gnomad SAS AF: 0.234

Gnomad FIN AF: 0.163

Gnomad MID AF: 0.153

Gnomad NFE AF: 0.160

Gnomad OTH AF: 0.201

GnomAD3 exomes AF: 0.179 AC: 40071 AN: 223790 Hom.: 4120 AF XY: 0.178 AC XY: 22000 AN XY: 123772

Gnomad AFR exome AF: 0.397

Gnomad AMR exome AF: 0.160

Gnomad ASJ exome AF: 0.172

Gnomad EAS exome AF: 0.119

Gnomad SAS exome AF: 0.217

Gnomad FIN exome AF: 0.170

Gnomad NFE exome AF: 0.158

Gnomad OTH exome AF: 0.171

GnomAD4 exome AF: 0.166 AC: 240171 AN: 1445460 Hom.: 21379 Cov.: 40 AF XY: 0.167 AC XY: 120004 AN XY: 719546

Gnomad4 AFR exome AF: 0.387

Gnomad4 AMR exome AF: 0.158

Gnomad4 ASJ exome AF: 0.169

Gnomad4 EAS exome AF: 0.139

Gnomad4 SAS exome AF: 0.219

Gnomad4 FIN exome AF: 0.164

Gnomad4 NFE exome AF: 0.156

Gnomad4 OTH exome AF: 0.177

GnomAD4 genome AF: 0.222 AC: 33711 AN: 152046 Hom.: 4501 Cov.: 33 AF XY: 0.220 AC XY: 16346 AN XY: 74334

Gnomad4 AFR AF: 0.379

Gnomad4 AMR AF: 0.153

Gnomad4 ASJ AF: 0.174

Gnomad4 EAS AF: 0.123

Gnomad4 SAS AF: 0.234

Gnomad4 FIN AF: 0.163

Gnomad4 NFE AF: 0.160

Gnomad4 OTH AF: 0.201

Alfa AF: 0.153 Hom.: 1395

Bravo AF: 0.227

ESP6500AA AF: 0.361 AC: 1563

ESP6500EA AF: 0.145 AC: 1231

ExAC AF: 0.180 AC: 21647

Asia WGS AF: 0.197 AC: 683 AN: 3464

ClinVar

Significance: Benign

Submissions summary: Benign:1 Other:1

Revision: criteria provided, single submitter

Submissions by phenotype

LOXL1-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jun 27, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Exfoliation syndrome, susceptibility to Other:1

risk factor, no assertion criteria provided

literature only

OMIM

May 01, 2009

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.66
BayesDel_addAF	Benign	-0.54	T
BayesDel_noAF	Benign	-0.40
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Benign	0.12	T
Eigen	Benign	-0.21
Eigen_PC	Benign	-0.077
FATHMM_MKL	Benign	0.66	D
LIST_S2	Benign	0.74	T
MetaRNN	Benign	0.0015	T
MetaSVM	Benign	-0.94	T
MutationAssessor	Benign	1.6	L
MutationTaster	Benign	0.012	P
PrimateAI	Pathogenic	0.87	D
PROVEAN	Benign	-1.2	N
REVEL	Benign	0.14
Sift	Uncertain	0.0020	D
Sift4G	Uncertain	0.040	D
Polyphen		0.0010	B
Vest4		0.032
ClinPred		0.018	T
GERP RS		3.2
Varity_R		0.26
gMVP		0.59

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

LitVar

Other links and lift over

dbSNP: rs3825942; hg19: chr15-74219582; COSMIC: COSV56093962; COSMIC: COSV56093962;