rs786204838

Variant names:

• chr2-74534149-C-T
• rs786204838
• NM_032603.5:c.2027G>A

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_032603.5(LOXL3):​c.2027G>A​(p.Cys676Tyr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,888 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (no stars).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: LOXL3 NM_032603.5 missense
• Clinical Significance: Uncertain significance no assertion criteria provided U:1
• Conservation: PhyloP100: 7.88
• Publications: 8 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: Genomics England PanelApp, Ambry Genetics
• autosomal recessive Stickler syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.982

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LOXL3	NM_032603.5	MANE Select	c.2027G>A	p.Cys676Tyr	missense	Exon 12 of 14	NP_115992.1	P58215-1
	LOXL3	NM_001289164.3		c.1592G>A	p.Cys531Tyr	missense	Exon 10 of 12	NP_001276093.1	P58215-3
	LOXL3	NM_001289165.2		c.944G>A	p.Cys315Tyr	missense	Exon 8 of 10	NP_001276094.1	P58215-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LOXL3	ENST00000264094.8	TSL:1 MANE Select	c.2027G>A	p.Cys676Tyr	missense	Exon 12 of 14	ENSP00000264094.3	P58215-1
	LOXL3	ENST00000946469.1		c.2027G>A	p.Cys676Tyr	missense	Exon 11 of 13	ENSP00000616528.1
	LOXL3	ENST00000853956.1		c.2027G>A	p.Cys676Tyr	missense	Exon 12 of 14	ENSP00000524015.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461888 Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1 AN XY: 727246

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53418

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1112008

Other (OTH) AF: 0.00 AC: 0 AN: 60396

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.31	D
BayesDel_noAF	Pathogenic	0.21
CADD	Pathogenic	31
DANN	Uncertain	1.0
DEOGEN2	Benign	0.21	T
Eigen	Pathogenic	0.91
Eigen_PC	Pathogenic	0.80
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	1.0	D
M_CAP	Uncertain	0.11	D
MetaRNN	Pathogenic	0.98	D
MetaSVM	Uncertain	-0.080	T
MutationAssessor	Pathogenic	3.4	M
PhyloP100		7.9
PrimateAI	Pathogenic	0.87	D
PROVEAN	Pathogenic	-10	D
REVEL	Pathogenic	0.70
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.97
MutPred		0.93		Gain of phosphorylation at C676 (P = 0.0716)
MVP		0.79
MPC		1.7
ClinPred		1.0	D
GERP RS		4.6
Varity_R		0.95
gMVP		0.96
Mutation Taster		=24/76	disease causing

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: rs786204838; hg19: chr2-74761276;