15-73927205-G-T

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_005576.4(LOXL1):c.422G>T(p.Arg141Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.326 in 1,591,266 control chromosomes in the GnomAD database, including 87,339 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as risk factor (no stars).

• Frequency:
  • Genomes: 𝑓 0.28 (6787 hom., cov: 33)
  • Exomes 𝑓: 0.33 (80552 hom.)
• Consequence: LOXL1 NM_005576.4 missense
• Clinical Significance: risk factor no assertion criteria provided O:1
• Conservation: PhyloP100: 1.83

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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0013831854).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.528 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LOXL1	NM_005576.4	c.422G>T	p.Arg141Leu	missense_variant	1/7	ENST00000261921.8
LOXL1-AS1	NR_040069.1	n.184+860C>A		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LOXL1	ENST00000261921.8	c.422G>T	p.Arg141Leu	missense_variant	1/7	1	NM_005576.4	P1
LOXL1-AS1	ENST00000685373.1	n.198+572C>A		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes AF: 0.285 AC: 43304 AN: 151898 Hom.: 6785 Cov.: 33

Gnomad AFR AF: 0.169

Gnomad AMI AF: 0.249

Gnomad AMR AF: 0.323

Gnomad ASJ AF: 0.256

Gnomad EAS AF: 0.545

Gnomad SAS AF: 0.329

Gnomad FIN AF: 0.309

Gnomad MID AF: 0.175

Gnomad NFE AF: 0.323

Gnomad OTH AF: 0.296

GnomAD3 exomes AF: 0.328 AC: 70580 AN: 215264 Hom.: 12359 AF XY: 0.329 AC XY: 39527 AN XY: 119978

Gnomad AFR exome AF: 0.171

Gnomad AMR exome AF: 0.307

Gnomad ASJ exome AF: 0.246

Gnomad EAS exome AF: 0.543

Gnomad SAS exome AF: 0.323

Gnomad FIN exome AF: 0.319

Gnomad NFE exome AF: 0.328

Gnomad OTH exome AF: 0.334

GnomAD4 exome AF: 0.330 AC: 475403 AN: 1439260 Hom.: 80552 Cov.: 39 AF XY: 0.330 AC XY: 236764 AN XY: 716454

Gnomad4 AFR exome AF: 0.168

Gnomad4 AMR exome AF: 0.313

Gnomad4 ASJ exome AF: 0.256

Gnomad4 EAS exome AF: 0.544

Gnomad4 SAS exome AF: 0.323

Gnomad4 FIN exome AF: 0.307

Gnomad4 NFE exome AF: 0.332

Gnomad4 OTH exome AF: 0.318

GnomAD4 genome AF: 0.285 AC: 43318 AN: 152006 Hom.: 6787 Cov.: 33 AF XY: 0.288 AC XY: 21386 AN XY: 74316

Gnomad4 AFR AF: 0.169

Gnomad4 AMR AF: 0.323

Gnomad4 ASJ AF: 0.256

Gnomad4 EAS AF: 0.545

Gnomad4 SAS AF: 0.330

Gnomad4 FIN AF: 0.309

Gnomad4 NFE AF: 0.323

Gnomad4 OTH AF: 0.296

Alfa AF: 0.276 Hom.: 2108

Bravo AF: 0.282

TwinsUK AF: 0.336 AC: 1245

ALSPAC AF: 0.340 AC: 1311

ESP6500AA AF: 0.160 AC: 678

ESP6500EA AF: 0.310 AC: 2569

ExAC AF: 0.318 AC: 37705

Asia WGS AF: 0.357 AC: 1239 AN: 3462

ClinVar

Significance: risk factor

Submissions summary: Other:1

Revision: no assertion criteria provided

Submissions by phenotype

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	0.58
BayesDel_addAF	Benign	-0.54	T
BayesDel_noAF	Benign	-0.40
Cadd	Pathogenic	27
Dann	Uncertain	1.0
DEOGEN2	Benign	0.12	T
Eigen	Uncertain	0.26
Eigen_PC	Uncertain	0.28
FATHMM_MKL	Uncertain	0.77	D
LIST_S2	Benign	0.66	T
MetaRNN	Benign	0.0014	T
MetaSVM	Benign	-0.91	T
MutationAssessor	Benign	1.9	L
MutationTaster	Benign	0.29	P
PrimateAI	Pathogenic	0.91	D
PROVEAN	Benign	-1.9	N
REVEL	Benign	0.080
Sift	Uncertain	0.0050	D
Sift4G	Uncertain	0.041	D
Polyphen		0.91	P
Vest4		0.047
ClinPred		0.016	T
GERP RS		4.1
Varity_R		0.26
gMVP		0.40

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: rs1048661; hg19: chr15-74219546; COSMIC: COSV56093367; COSMIC: COSV56093367;