chr2-74534412-T-A

Variant names:

• chr2-74534412-T-A
• rs17010021
• NM_032603.5:c.1843A>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_032603.5(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 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 NM_032603.5 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 1.44
• Publications: 32 publications found

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]

LOXL3 Gene-Disease associations (from GenCC):

• myopia 28, autosomal recessive

  Inheritance: AR, Unknown Classification: STRONG, LIMITED Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)
• Stickler syndrome

  Inheritance: AR Classification: MODERATE, LIMITED Submitted by: Ambry Genetics, Genomics England PanelApp
• autosomal recessive Stickler syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -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 VariationId 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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_032603.5. 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
	LOXL3	NM_032603.5	MANE Select	c.1843A>T	p.Ile615Phe	missense	Exon 11 of 14	NP_115992.1
	LOXL3	NM_001289164.3		c.1408A>T	p.Ile470Phe	missense	Exon 9 of 12	NP_001276093.1
	LOXL3	NM_001289165.2		c.760A>T	p.Ile254Phe	missense	Exon 7 of 10	NP_001276094.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LOXL3	ENST00000264094.8	TSL:1 MANE Select	c.1843A>T	p.Ile615Phe	missense	Exon 11 of 14	ENSP00000264094.3
	LOXL3	ENST00000409549.5	TSL:2	c.1675A>T	p.Ile559Phe	missense	Exon 9 of 12	ENSP00000386696.1
	LOXL3	ENST00000393937.6	TSL:5	c.1408A>T	p.Ile470Phe	missense	Exon 9 of 12	ENSP00000377512.2

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

GnomAD2 exomes AF: 0.0825 AC: 20741 AN: 251482 AF XY: 0.0821

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 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

African (AFR) AF: 0.0231 AC: 773 AN: 33480

American (AMR) AF: 0.107 AC: 4780 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0359 AC: 938 AN: 26136

East Asian (EAS) AF: 0.376 AC: 14934 AN: 39696

South Asian (SAS) AF: 0.122 AC: 10527 AN: 86254

European-Finnish (FIN) AF: 0.0464 AC: 2480 AN: 53420

Middle Eastern (MID) AF: 0.0265 AC: 153 AN: 5768

European-Non Finnish (NFE) AF: 0.0376 AC: 41782 AN: 1111964

Other (OTH) AF: 0.0603 AC: 3640 AN: 60394

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

African (AFR) AF: 0.0274 AC: 1138 AN: 41556

American (AMR) AF: 0.0917 AC: 1402 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.0441 AC: 153 AN: 3470

East Asian (EAS) AF: 0.339 AC: 1755 AN: 5174

South Asian (SAS) AF: 0.138 AC: 667 AN: 4830

European-Finnish (FIN) AF: 0.0467 AC: 496 AN: 10616

Middle Eastern (MID) AF: 0.0238 AC: 7 AN: 294

European-Non Finnish (NFE) AF: 0.0373 AC: 2540 AN: 68020

Other (OTH) AF: 0.0577 AC: 122 AN: 2114

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

Oct 16, 2019

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 29802726)

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

not specified Benign:1

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

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
Eigen	Uncertain	0.32
Eigen_PC	Uncertain	0.30
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.96	D
MetaRNN	Benign	0.0029	T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	1.4	L
PhyloP100		1.4
PrimateAI	Uncertain	0.63	T
PROVEAN	Uncertain	-3.3	D
REVEL	Benign	0.14
Sift	Uncertain	0.0020	D
Sift4G	Uncertain	0.0070	D
Polyphen		0.92	P
Vest4		0.77
MPC		1.5
ClinPred		0.017	T
GERP RS		3.7
Varity_R		0.62
gMVP		0.79
Mutation Taster		=75/25	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: rs17010021; hg19: chr2-74761539; COSMIC: COSV51211033; COSMIC: COSV51211033;