rs1367291930

Variant names:

• chr2-74532729-G-A
• rs1367291930
• NM_032603.5:c.*877C>T

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 2P and 6B. PM2 BP4_Strong BP6_Moderate

The NM_032603.5(LOXL3):​c.*877C>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000685 in 1,460,384 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000068 (0 hom.)
• Consequence: LOXL3 NM_032603.5 3_prime_UTR
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 1.57
• Publications: 0 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]

HTRA2 (HGNC:14348): (HtrA serine peptidase 2) This gene encodes a serine protease. The protein has been localized in the endoplasmic reticulum and interacts with an alternatively spliced form of mitogen-activated protein kinase 14. The protein has also been localized to the mitochondria with release to the cytosol following apoptotic stimulus. The protein is thought to induce apoptosis by binding the apoptosis inhibitory protein baculoviral IAP repeat-containing 4. Nuclear localization of this protein has also been observed. Alternate splicing of this gene results in multiple transcript variants encoding different isoforms. [provided by RefSeq, Mar 2016]

HTRA2 Gene-Disease associations (from GenCC):

• 3-methylglutaconic aciduria type 8

  Inheritance: AR Classification: DEFINITIVE, STRONG, LIMITED Submitted by: ClinGen, Labcorp Genetics (formerly Invitae), G2P

ACMG classification

Our verdict: Likely_benign. The variant received -4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.77).
• BP6: Variant 2-74532729-G-A is Benign according to our data. Variant chr2-74532729-G-A is described in ClinVar as Likely_benign. ClinVar VariationId is 2966217.Status of the report is criteria_provided_single_submitter, 1 stars.

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.*877C>T		3_prime_UTR	Exon 14 of 14	NP_115992.1	P58215-1
	HTRA2	NM_013247.5	MANE Select	c.1211+15G>A		intron	N/A	NP_037379.1	O43464-1
	LOXL3	NM_001289164.3		c.*877C>T		3_prime_UTR	Exon 12 of 12	NP_001276093.1	P58215-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LOXL3	ENST00000264094.8	TSL:1 MANE Select	c.*877C>T		3_prime_UTR	Exon 14 of 14	ENSP00000264094.3	P58215-1
	HTRA2	ENST00000258080.8	TSL:1 MANE Select	c.1211+15G>A		intron	N/A	ENSP00000258080.3	O43464-1
	HTRA2	ENST00000437202.2	TSL:1	c.1146-91G>A		intron	N/A	ENSP00000399166.2	O43464-3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000685 AC: 10 AN: 1460384 Hom.: 0 Cov.: 30 AF XY: 0.00000550 AC XY: 4 AN XY: 726626

African (AFR) AF: 0.00 AC: 0 AN: 33436

American (AMR) AF: 0.00 AC: 0 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26134

East Asian (EAS) AF: 0.00 AC: 0 AN: 39694

South Asian (SAS) AF: 0.00 AC: 0 AN: 86214

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

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5690

European-Non Finnish (NFE) AF: 0.00000900 AC: 10 AN: 1110726

Other (OTH) AF: 0.00 AC: 0 AN: 60352

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000936 Hom.: 0

Bravo AF: 0.00000378

ClinVar

ClinVar submissions as Germline

Significance: Likely benign

Revision: criteria provided, single submitter

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.77
CADD	Benign	9.2
DANN	Benign	0.71
PhyloP100		1.6

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: rs1367291930; hg19: chr2-74759856;