rs1057519080

Positions:

• chr2-74532919-GGCAGT-G

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PVS1_Moderate PM2 PP5

The NM_013247.5(HTRA2):​c.1316_1320del​(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). Synonymous variant affecting the same amino acid position (i.e. A438A) has been classified as Likely benign.

• 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

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 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 0.0472 CDS is truncated, and there are 1 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 id is 372210.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HTRA2	NM_013247.5	c.1316_1320del	p.Val439AspfsTer15	frameshift_variant	8/8	ENST00000258080.8
LOXL3	NM_032603.5	c.*682_*686del		3_prime_UTR_variant	14/14	ENST00000264094.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HTRA2	ENST00000258080.8	c.1316_1320del	p.Val439AspfsTer15	frameshift_variant	8/8	1	NM_013247.5	P1
LOXL3	ENST00000264094.8	c.*682_*686del		3_prime_UTR_variant	14/14	1	NM_032603.5	P1

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

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

3-methylglutaconic aciduria type 8 Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Dec 17, 2016

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Computational scores

Source: dbNSFP v4.3

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs1057519080; hg19: chr2-74760046;