2-74532919-GGCAGT-G

Variant names:

• chr2-74532918-TGGCAG-TG
• NM_013247.5:c.1312_1315delGCAG

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PVS1_Moderate PM2

The NM_013247.5(HTRA2):​c.1312_1315delGCAG​(p.Ala438CysfsTer10) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. 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: Not reported in ClinVar
• Conservation: PhyloP100: 2.81
• 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]

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: Genomics England PanelApp, Ambry Genetics
• autosomal recessive Stickler syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Uncertain_significance. The variant received 4 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 2 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HTRA2	NM_013247.5	MANE Select	c.1312_1315delGCAG	p.Ala438CysfsTer10	frameshift	Exon 8 of 8	NP_037379.1	O43464-1
	LOXL3	NM_032603.5	MANE Select	c.*683_*686delCTGC		3_prime_UTR	Exon 14 of 14	NP_115992.1	P58215-1
	HTRA2	NM_001321727.1		c.1246_1249delGCAG	p.Ala416CysfsTer10	frameshift	Exon 7 of 7	NP_001308656.1	O43464-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HTRA2	ENST00000258080.8	TSL:1 MANE Select	c.1312_1315delGCAG	p.Ala438CysfsTer10	frameshift	Exon 8 of 8	ENSP00000258080.3	O43464-1
	HTRA2	ENST00000437202.2	TSL:1	c.1246_1249delGCAG	p.Ala416CysfsTer10	frameshift	Exon 7 of 7	ENSP00000399166.2	O43464-3
	HTRA2	ENST00000352222.7	TSL:1	c.1021_1024delGCAG	p.Ala341CysfsTer10	frameshift	Exon 6 of 6	ENSP00000312893.3	O43464-2

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

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		2.8

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

hg19: chr2-74760045;