10-98253620-T-C

Variant names:

• chr10-98253620-T-C
• NM_032211.7:c.1768A>G

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_032211.7(LOXL4):​c.1768A>G​(p.Asn590Asp) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,890 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 (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: LOXL4 NM_032211.7 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 8.02

Genes affected

LOXL4 (HGNC:17171): (lysyl oxidase like 4) This gene encodes a member of the lysyl oxidase gene family. The prototypic member of the family is essential to the biogenesis of connective tissue, encoding an extracellular copper-dependent amine oxidase that catalyses the first step in the formation of crosslinks in collagens and elastin. 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. [provided by RefSeq, Jul 2008]

ENSG00000230928 (HGNC:):

ACMG classification

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.957

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LOXL4	NM_032211.7	c.1768A>G	p.Asn590Asp	missense_variant	Exon 11 of 15	ENST00000260702.4	NP_115587.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LOXL4	ENST00000260702.4	c.1768A>G	p.Asn590Asp	missense_variant	Exon 11 of 15	1	NM_032211.7	ENSP00000260702.3
ENSG00000230928	ENST00000433374.1	n.180+1418T>C		intron_variant	Intron 1 of 1	1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461890 Hom.: 0 Cov.: 33 AF XY: 0.00000275 AC XY: 2 AN XY: 727246

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 8.99e-7

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Dec 11, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1768A>G (p.N590D) alteration is located in exon 11 (coding exon 10) of the LOXL4 gene. This alteration results from a A to G substitution at nucleotide position 1768, causing the asparagine (N) at amino acid position 590 to be replaced by an aspartic acid (D). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.82
BayesDel_addAF	Uncertain	0.012	T
BayesDel_noAF	Benign	-0.22
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Benign	0.34	T
Eigen	Pathogenic	0.87
Eigen_PC	Pathogenic	0.78
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Uncertain	0.95	D
M_CAP	Benign	0.033	D
MetaRNN	Pathogenic	0.96	D
MetaSVM	Uncertain	-0.21	T
MutationAssessor	Pathogenic	3.4	M
PrimateAI	Uncertain	0.59	T
PROVEAN	Pathogenic	-4.7	D
REVEL	Uncertain	0.61
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.0050	D
Polyphen		1.0	D
Vest4		0.96
MutPred		0.83		Loss of MoRF binding (P = 0.0499);
MVP		0.71
MPC		0.57
ClinPred		1.0	D
GERP RS		4.9
Varity_R		0.90
gMVP		0.80

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr10-100013377;