15-73927659-C-T

Variant summary

Our verdict is Benign. Variant got -15 ACMG points: 0P and 15B. BP4_Strong BP6_Moderate BP7 BS1 BS2

The NM_005576.4(LOXL1):c.876C>T(p.Asp292=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0343 in 1,487,556 control chromosomes in the GnomAD database, including 1,019 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.025 (58 hom., cov: 33)
  • Exomes 𝑓: 0.035 (961 hom.)
• Consequence: LOXL1 NM_005576.4 synonymous
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.807

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 -15 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BP6: Variant 15-73927659-C-T is Benign according to our data. Variant chr15-73927659-C-T is described in ClinVar as [Benign]. Clinvar id is 3038417.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=-0.807 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0248 (3771/152144) while in subpopulation NFE AF= 0.0359 (2440/67958). AF 95% confidence interval is 0.0347. There are 58 homozygotes in gnomad4. There are 1861 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 58 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LOXL1	NM_005576.4	c.876C>T	p.Asp292=	synonymous_variant	1/7	ENST00000261921.8
LOXL1-AS1	NR_040069.1	n.184+406G>A		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LOXL1	ENST00000261921.8	c.876C>T	p.Asp292=	synonymous_variant	1/7	1	NM_005576.4	P1
LOXL1-AS1	ENST00000685373.1	n.198+118G>A		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes AF: 0.0248 AC: 3773 AN: 152036 Hom.: 58 Cov.: 33

Gnomad AFR AF: 0.00662

Gnomad AMI AF: 0.0318

Gnomad AMR AF: 0.0225

Gnomad ASJ AF: 0.0109

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.0120

Gnomad FIN AF: 0.0498

Gnomad MID AF: 0.00637

Gnomad NFE AF: 0.0359

Gnomad OTH AF: 0.0292

GnomAD3 exomes AF: 0.0247 AC: 2073 AN: 83938 Hom.: 44 AF XY: 0.0244 AC XY: 1166 AN XY: 47884

Gnomad AFR exome AF: 0.00783

Gnomad AMR exome AF: 0.0150

Gnomad ASJ exome AF: 0.00874

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0132

Gnomad FIN exome AF: 0.0562

Gnomad NFE exome AF: 0.0385

Gnomad OTH exome AF: 0.0266

GnomAD4 exome AF: 0.0354 AC: 47259 AN: 1335412 Hom.: 961 Cov.: 34 AF XY: 0.0343 AC XY: 22576 AN XY: 658576

Gnomad4 AFR exome AF: 0.00549

Gnomad4 AMR exome AF: 0.0169

Gnomad4 ASJ exome AF: 0.00891

Gnomad4 EAS exome AF: 0.0000341

Gnomad4 SAS exome AF: 0.0114

Gnomad4 FIN exome AF: 0.0492

Gnomad4 NFE exome AF: 0.0400

Gnomad4 OTH exome AF: 0.0274

GnomAD4 genome AF: 0.0248 AC: 3771 AN: 152144 Hom.: 58 Cov.: 33 AF XY: 0.0250 AC XY: 1861 AN XY: 74370

Gnomad4 AFR AF: 0.00660

Gnomad4 AMR AF: 0.0223

Gnomad4 ASJ AF: 0.0109

Gnomad4 EAS AF: 0.000194

Gnomad4 SAS AF: 0.0120

Gnomad4 FIN AF: 0.0498

Gnomad4 NFE AF: 0.0359

Gnomad4 OTH AF: 0.0289

Alfa AF: 0.0268 Hom.: 33

Bravo AF: 0.0229

Asia WGS AF: 0.00609 AC: 21 AN: 3462

ClinVar

Significance: Benign

Submissions summary: Benign: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

Apr 25, 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). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
Cadd	Benign	3.5
Dann	Benign	0.90

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: rs41429348; hg19: chr15-74220000;