rs78803776

Positions:

• chr15-73927258-T-G

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6 BA1

The NM_005576.4(LOXL1):​c.475T>G​(p.Ser159Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00821 in 1,601,216 control chromosomes in the GnomAD database, including 913 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (no stars).

• Frequency:
  • Genomes: 𝑓 0.045 (509 hom., cov: 33)
  • Exomes 𝑓: 0.0043 (404 hom.)
• Consequence: LOXL1 NM_005576.4 missense
• Clinical Significance: Benign no assertion criteria provided B:1
• Conservation: PhyloP100: 0.985

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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0016031265).
• BP6: Variant 15-73927258-T-G is Benign according to our data. Variant chr15-73927258-T-G is described in ClinVar as [Benign]. Clinvar id is 3055709.Status of the report is no_assertion_criteria_provided, 0 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.154 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LOXL1	NM_005576.4	c.475T>G	p.Ser159Ala	missense_variant	1/7	ENST00000261921.8	NP_005567.2
LOXL1-AS1	NR_040069.1	n.184+807A>C		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LOXL1	ENST00000261921.8	c.475T>G	p.Ser159Ala	missense_variant	1/7	1	NM_005576.4	ENSP00000261921	P1
LOXL1-AS1	ENST00000685373.1	n.198+519A>C		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes AF: 0.0451 AC: 6861 AN: 152084 Hom.: 508 Cov.: 33

Gnomad AFR AF: 0.158

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0143

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.000530

Gnomad OTH AF: 0.0325

GnomAD3 exomes AF: 0.0106 AC: 2413 AN: 227168 Hom.: 175 AF XY: 0.00763 AC XY: 956 AN XY: 125364

Gnomad AFR exome AF: 0.154

Gnomad AMR exome AF: 0.00676

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000338

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000443

Gnomad OTH exome AF: 0.00355

GnomAD4 exome AF: 0.00433 AC: 6269 AN: 1449024 Hom.: 404 Cov.: 36 AF XY: 0.00365 AC XY: 2632 AN XY: 721184

Gnomad4 AFR exome AF: 0.153

Gnomad4 AMR exome AF: 0.00845

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000398

Gnomad4 FIN exome AF: 0.0000431

Gnomad4 NFE exome AF: 0.000239

Gnomad4 OTH exome AF: 0.00963

GnomAD4 genome AF: 0.0451 AC: 6870 AN: 152192 Hom.: 509 Cov.: 33 AF XY: 0.0431 AC XY: 3209 AN XY: 74418

Gnomad4 AFR AF: 0.158

Gnomad4 AMR AF: 0.0142

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000414

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000515

Gnomad4 OTH AF: 0.0322

Alfa AF: 0.0128 Hom.: 46

Bravo AF: 0.0513

ESP6500AA AF: 0.143 AC: 620

ESP6500EA AF: 0.000118 AC: 1

ExAC AF: 0.0136 AC: 1642

Asia WGS AF: 0.00785 AC: 28 AN: 3454

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: no assertion criteria provided

Submissions by phenotype

LOXL1-related disorder Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jan 24, 2020

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
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.70	T
BayesDel_noAF	Benign	-0.64
CADD	Benign	21
DANN	Uncertain	0.99
DEOGEN2	Benign	0.078	T
Eigen	Benign	-0.32
Eigen_PC	Benign	-0.23
FATHMM_MKL	Benign	0.56	D
LIST_S2	Benign	0.43	T
MetaRNN	Benign	0.0016	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.9	L
MutationTaster	Benign	0.029	P
PrimateAI	Pathogenic	0.85	D
PROVEAN	Benign	-0.70	N
REVEL	Benign	0.015
Sift	Benign	0.46	T
Sift4G	Benign	0.28	T
Polyphen		0.18	B
Vest4		0.090
ClinPred		0.0040	T
GERP RS		2.9
Varity_R		0.071
gMVP		0.57

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: rs78803776; hg19: chr15-74219599;