NM_005576.4:c.422G>T

Variant names:

• chr15-73927205-G-T
• rs1048661
• NM_005576.4:c.422G>T

Variant summary

Our verdict is Benign. The variant received -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
• Publications: 171 publications found

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

Our verdict: Benign. The variant received -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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005576.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LOXL1	NM_005576.4	MANE Select	c.422G>T	p.Arg141Leu	missense	Exon 1 of 7	NP_005567.2
	LOXL1-AS1	NR_040066.1		n.133+449C>A		intron	N/A
	LOXL1-AS1	NR_040067.1		n.133+449C>A		intron	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LOXL1	ENST00000261921.8	TSL:1 MANE Select	c.422G>T	p.Arg141Leu	missense	Exon 1 of 7	ENSP00000261921.7
	LOXL1	ENST00000856631.1		c.422G>T	p.Arg141Leu	missense	Exon 1 of 6	ENSP00000526690.1
	LOXL1	ENST00000566011.5	TSL:5	n.422G>T		non_coding_transcript_exon	Exon 1 of 8	ENSP00000457827.1

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

GnomAD2 exomes AF: 0.328 AC: 70580 AN: 215264 AF XY: 0.329

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 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

African (AFR) AF: 0.168 AC: 5334 AN: 31672

American (AMR) AF: 0.313 AC: 13639 AN: 43628

Ashkenazi Jewish (ASJ) AF: 0.256 AC: 6566 AN: 25690

East Asian (EAS) AF: 0.544 AC: 20947 AN: 38472

South Asian (SAS) AF: 0.323 AC: 27339 AN: 84650

European-Finnish (FIN) AF: 0.307 AC: 13296 AN: 43242

Middle Eastern (MID) AF: 0.263 AC: 1495 AN: 5682

European-Non Finnish (NFE) AF: 0.332 AC: 367759 AN: 1106460

Other (OTH) AF: 0.318 AC: 19028 AN: 59764

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

African (AFR) AF: 0.169 AC: 7000 AN: 41524

American (AMR) AF: 0.323 AC: 4939 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.256 AC: 887 AN: 3464

East Asian (EAS) AF: 0.545 AC: 2799 AN: 5138

South Asian (SAS) AF: 0.330 AC: 1595 AN: 4834

European-Finnish (FIN) AF: 0.309 AC: 3258 AN: 10558

Middle Eastern (MID) AF: 0.188 AC: 55 AN: 292

European-Non Finnish (NFE) AF: 0.323 AC: 21934 AN: 67892

Other (OTH) AF: 0.296 AC: 624 AN: 2108

Alfa AF: 0.290 Hom.: 3624

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

ClinVar submissions as Germline

Significance: risk factor

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
-	-	-	Exfoliation syndrome, susceptibility to (1)

Computational scores

Source: dbNSFP v4.9

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
PhyloP100		1.8
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
Mutation Taster		=89/11	polymorphism (auto)

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

Other links and lift over

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