rs1057519082

Variant names:

• chr2-74530927-TGC-CAT
• rs1057519082
• NM_013247.5:c.728_730delTGCinsCAT

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 1P and 0B. PP5

The NM_013247.5(HTRA2):​c.728_730delTGCinsCAT​(p.LeuPro243ProSer) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. It is difficult to determine the true allele frequency of this variant because it is of type MNV, and the frequency of such variant types in population databases may be underestimated and unreliable. Variant has been reported in ClinVar as Pathogenic (no stars).

• Frequency: Genomes: not found (cov: 32)
• Consequence: HTRA2 NM_013247.5 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 6.27
• Publications: 0 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]

HTRA2 Gene-Disease associations (from GenCC):

• 3-methylglutaconic aciduria type 8

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

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PP5: Variant 2-74530927-TGC-CAT is Pathogenic according to our data. Variant chr2-74530927-TGC-CAT is described in ClinVar as Pathogenic. ClinVar VariationId is 372212.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HTRA2	NM_013247.5	c.728_730delTGCinsCAT	p.LeuPro243ProSer	missense_variant		ENST00000258080.8	NP_037379.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HTRA2	ENST00000258080.8	c.728_730delTGCinsCAT	p.LeuPro243ProSer	missense_variant		1	NM_013247.5	ENSP00000258080.3

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

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

3-methylglutaconic aciduria type 8 Pathogenic:1

Jul 20, 2017

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		6.3
Mutation Taster		=38/162	disease causing

Splicing

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

Other links and lift over

dbSNP: rs1057519082; hg19: chr2-74758054;