rs17010021

Positions:

• chr2-74534412-T-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The ENST00000264094.8(LOXL3):​c.1843A>T​(p.Ile615Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0547 in 1,614,118 control chromosomes in the GnomAD database, including 5,524 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I615T) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.055 (538 hom., cov: 33)
  • Exomes 𝑓: 0.055 (4986 hom.)
• Consequence: LOXL3 ENST00000264094.8 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 1.44

Genes affected

LOXL3 (HGNC:13869): (lysyl oxidase like 3) This gene encodes a lysyl oxidase, which likely functions as an amine oxidase and plays a role in the formation of crosslinks in collagens and elastin. Deletion of the related gene in mouse causes neonatal mortality with cleft palate, spine deformity, and defects in collagen organization. A mutation in this gene was found in a family with Stickler syndrome. [provided by RefSeq, Sep 2016]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0029302537).
• BP6: Variant 2-74534412-T-A is Benign according to our data. Variant chr2-74534412-T-A is described in ClinVar as [Benign]. Clinvar id is 262091.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.326 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LOXL3	NM_032603.5	c.1843A>T	p.Ile615Phe	missense_variant	11/14	ENST00000264094.8	NP_115992.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LOXL3	ENST00000264094.8	c.1843A>T	p.Ile615Phe	missense_variant	11/14	1	NM_032603.5	ENSP00000264094	P1

Frequencies

GnomAD3 genomes AF: 0.0545 AC: 8299 AN: 152164 Hom.: 538 Cov.: 33

Gnomad AFR AF: 0.0274

Gnomad AMI AF: 0.0230

Gnomad AMR AF: 0.0916

Gnomad ASJ AF: 0.0441

Gnomad EAS AF: 0.340

Gnomad SAS AF: 0.138

Gnomad FIN AF: 0.0467

Gnomad MID AF: 0.0253

Gnomad NFE AF: 0.0373

Gnomad OTH AF: 0.0564

GnomAD3 exomes AF: 0.0825 AC: 20741 AN: 251482 Hom.: 1821 AF XY: 0.0821 AC XY: 11154 AN XY: 135910

Gnomad AFR exome AF: 0.0274

Gnomad AMR exome AF: 0.109

Gnomad ASJ exome AF: 0.0347

Gnomad EAS exome AF: 0.350

Gnomad SAS exome AF: 0.127

Gnomad FIN exome AF: 0.0467

Gnomad NFE exome AF: 0.0388

Gnomad OTH exome AF: 0.0697

GnomAD4 exome AF: 0.0547 AC: 80007 AN: 1461836 Hom.: 4986 Cov.: 33 AF XY: 0.0562 AC XY: 40891 AN XY: 727218

Gnomad4 AFR exome AF: 0.0231

Gnomad4 AMR exome AF: 0.107

Gnomad4 ASJ exome AF: 0.0359

Gnomad4 EAS exome AF: 0.376

Gnomad4 SAS exome AF: 0.122

Gnomad4 FIN exome AF: 0.0464

Gnomad4 NFE exome AF: 0.0376

Gnomad4 OTH exome AF: 0.0603

GnomAD4 genome AF: 0.0545 AC: 8301 AN: 152282 Hom.: 538 Cov.: 33 AF XY: 0.0584 AC XY: 4346 AN XY: 74470

Gnomad4 AFR AF: 0.0274

Gnomad4 AMR AF: 0.0917

Gnomad4 ASJ AF: 0.0441

Gnomad4 EAS AF: 0.339

Gnomad4 SAS AF: 0.138

Gnomad4 FIN AF: 0.0467

Gnomad4 NFE AF: 0.0373

Gnomad4 OTH AF: 0.0577

Alfa AF: 0.0382 Hom.: 43

Bravo AF: 0.0540

TwinsUK AF: 0.0429 AC: 159

ALSPAC AF: 0.0358 AC: 138

ESP6500AA AF: 0.0286 AC: 126

ESP6500EA AF: 0.0359 AC: 309

ExAC AF: 0.0803 AC: 9748

Asia WGS AF: 0.222 AC: 771 AN: 3478

EpiCase AF: 0.0350

EpiControl AF: 0.0359

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	GeneDx	Oct 16, 2019	This variant is associated with the following publications: (PMID: 29802726) -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.76
BayesDel_addAF	Benign	-0.50	T
BayesDel_noAF	Benign	-0.34
CADD	Uncertain	26
DANN	Uncertain	0.98
DEOGEN2	Benign	0.15	T;.;T;.
Eigen	Uncertain	0.32
Eigen_PC	Uncertain	0.30
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.96	D;D;D;D
MetaRNN	Benign	0.0029	T;T;T;T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	1.4	L;.;.;.
MutationTaster	Benign	0.00013	P;P;P;P;P
PrimateAI	Uncertain	0.63	T
PROVEAN	Uncertain	-3.3	D;D;D;D
REVEL	Benign	0.14
Sift	Uncertain	0.0020	D;D;D;D
Sift4G	Uncertain	0.0070	D;D;D;D
Polyphen		0.92	P;.;D;D
Vest4		0.77
MPC		1.5
ClinPred		0.017	T
GERP RS		3.7
Varity_R		0.62
gMVP		0.79

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: rs17010021; hg19: chr2-74761539; COSMIC: COSV51211033; COSMIC: COSV51211033;