15-73927659-C-T

Variant names:

• chr15-73927659-C-T
• rs41429348
• NM_005576.4:c.876C>T

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6 BP7 BS1 BS2

The NM_005576.4(LOXL1):​c.876C>T​(p.Asp292Asp) 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 (no stars).

• Frequency:
  • Genomes: 𝑓 0.025 (58 hom., cov: 33)
  • Exomes 𝑓: 0.035 (961 hom.)
• Consequence: LOXL1 NM_005576.4 synonymous
• Clinical Significance: Benign no assertion criteria provided B:1
• Conservation: PhyloP100: -0.807
• Publications: 9 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 -14 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 VariationId is 3038417.Status of the report is no_assertion_criteria_provided, 0 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 the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 58 AR gene

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LOXL1	NM_005576.4	MANE Select	c.876C>T	p.Asp292Asp	synonymous	Exon 1 of 7	NP_005567.2
	LOXL1-AS1	NR_040066.1		n.128G>A		non_coding_transcript_exon	Exon 1 of 4
	LOXL1-AS1	NR_040067.1		n.128G>A		non_coding_transcript_exon	Exon 1 of 4

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LOXL1	ENST00000261921.8	TSL:1 MANE Select	c.876C>T	p.Asp292Asp	synonymous	Exon 1 of 7	ENSP00000261921.7
	LOXL1-AS1	ENST00000562739.6	TSL:4	n.39G>A		non_coding_transcript_exon	Exon 1 of 3
	LOXL1-AS1	ENST00000564963.1	TSL:4	n.37G>A		non_coding_transcript_exon	Exon 1 of 4

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

GnomAD2 exomes AF: 0.0247 AC: 2073 AN: 83938 AF XY: 0.0244

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 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

African (AFR) AF: 0.00549 AC: 149 AN: 27120

American (AMR) AF: 0.0169 AC: 484 AN: 28714

Ashkenazi Jewish (ASJ) AF: 0.00891 AC: 211 AN: 23686

East Asian (EAS) AF: 0.0000341 AC: 1 AN: 29294

South Asian (SAS) AF: 0.0114 AC: 847 AN: 74228

European-Finnish (FIN) AF: 0.0492 AC: 1642 AN: 33352

Middle Eastern (MID) AF: 0.0132 AC: 71 AN: 5396

European-Non Finnish (NFE) AF: 0.0400 AC: 42330 AN: 1057920

Other (OTH) AF: 0.0274 AC: 1524 AN: 55702

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

African (AFR) AF: 0.00660 AC: 274 AN: 41538

American (AMR) AF: 0.0223 AC: 341 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.0109 AC: 38 AN: 3472

East Asian (EAS) AF: 0.000194 AC: 1 AN: 5158

South Asian (SAS) AF: 0.0120 AC: 58 AN: 4828

European-Finnish (FIN) AF: 0.0498 AC: 527 AN: 10584

Middle Eastern (MID) AF: 0.00685 AC: 2 AN: 292

European-Non Finnish (NFE) AF: 0.0359 AC: 2440 AN: 67958

Other (OTH) AF: 0.0289 AC: 61 AN: 2108

Alfa AF: 0.0267 Hom.: 35

Bravo AF: 0.0229

Asia WGS AF: 0.00609 AC: 21 AN: 3462

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
-	-	1	LOXL1-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	3.5
DANN	Benign	0.90
PhyloP100		-0.81
Mutation Taster		=100/0	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: rs41429348; hg19: chr15-74220000; COSMIC: COSV107246663; COSMIC: COSV107246663;