rs1057519080

Variant names:

• chr2-74532919-GGCAGT-G
• rs1057519080
• NM_013247.5:c.1316_1320delTGCAG

Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 5P and 0B. PVS1_Moderate PM2 PP5

The NM_013247.5(HTRA2):​c.1316_1320delTGCAG​(p.Val439AspfsTer15) variant causes a frameshift change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (no stars).

• Frequency: Genomes: not found (cov: 32)
• Consequence: HTRA2 NM_013247.5 frameshift
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 5.05
• Publications: 2 publications found

Genes affected

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]

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: Uncertain_significance. The variant received 5 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. Fraction of 0.0443 CDS is truncated, and there are 2 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 2-74532919-GGCAGT-G is Pathogenic according to our data. Variant chr2-74532919-GGCAGT-G is described in ClinVar as Pathogenic. ClinVar VariationId is 372210.Status of the report is no_assertion_criteria_provided, 0 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_013247.5. 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
	HTRA2	NM_013247.5	MANE Select	c.1316_1320delTGCAG	p.Val439AspfsTer15	frameshift	Exon 8 of 8	NP_037379.1
	LOXL3	NM_032603.5	MANE Select	c.*682_*686delACTGC		3_prime_UTR	Exon 14 of 14	NP_115992.1
	HTRA2	NM_001321727.1		c.1250_1254delTGCAG	p.Val417AspfsTer15	frameshift	Exon 7 of 7	NP_001308656.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HTRA2	ENST00000258080.8	TSL:1 MANE Select	c.1316_1320delTGCAG	p.Val439AspfsTer15	frameshift	Exon 8 of 8	ENSP00000258080.3
	HTRA2	ENST00000437202.2	TSL:1	c.1250_1254delTGCAG	p.Val417AspfsTer15	frameshift	Exon 7 of 7	ENSP00000399166.2
	HTRA2	ENST00000352222.7	TSL:1	c.1025_1029delTGCAG	p.Val342AspfsTer15	frameshift	Exon 6 of 6	ENSP00000312893.3

Frequencies

GnomAD3 genomes Cov.: 32

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions as Germline

Significance: Pathogenic

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
1	-	-	3-methylglutaconic aciduria type 8 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		5.1
Mutation Taster		=8/192	disease causing (ClinVar)

Splicing

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

Other links and lift over

dbSNP: rs1057519080; hg19: chr2-74760046;