rs786205670

Variant names:

• chr20-45892873-AC-A
• rs786205670
• NM_000308.4:c.595delC

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PVS1 PM2 PP5_Moderate

The NM_000308.4(CTSA):​c.595delC​(p.Leu199PhefsTer59) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Likely pathogenic (★). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 32)
• Consequence: CTSA NM_000308.4 frameshift
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 1.79
• Publications: 1 publications found

Genes affected

CTSA (HGNC:9251): (cathepsin A) This gene encodes a member of the peptidase S10 family of serine carboxypeptidases. Alternative splicing results in multiple transcript variants, at least one of which encodes a preproprotein that is proteolytically processed to generate two chains that comprise the heterodimeric active enzyme. This enzyme possesses deamidase, esterase and carboxypeptidase activities and acts as a scaffold in the lysosomal multienzyme complex. Mutations in this gene are associated with galactosialidosis. [provided by RefSeq, Nov 2015]

CTSA Gene-Disease associations (from GenCC):

• galactosialidosis

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: ClinGen, Labcorp Genetics (formerly Invitae), Orphanet, Genomics England PanelApp, Illumina, G2P

ENSG00000271984 (HGNC:):

ACMG classification

Our verdict: Pathogenic. The variant received 12 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 20-45892873-AC-A is Pathogenic according to our data. Variant chr20-45892873-AC-A is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 190458.Status of the report is criteria_provided_single_submitter, 1 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000308.4. 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
	CTSA	NM_000308.4	MANE Select	c.595delC	p.Leu199PhefsTer59	frameshift	Exon 6 of 15	NP_000299.3	P10619-1
	CTSA	NM_001127695.3		c.595delC	p.Leu199PhefsTer59	frameshift	Exon 6 of 15	NP_001121167.1	P10619-1
	CTSA	NM_001167594.3		c.544delC	p.Leu182PhefsTer59	frameshift	Exon 5 of 14	NP_001161066.2	P10619-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CTSA	ENST00000646241.3	MANE Select	c.595delC	p.Leu199PhefsTer59	frameshift	Exon 6 of 15	ENSP00000493613.2	P10619-1
	CTSA	ENST00000372484.8	TSL:1	c.649delC	p.Leu217PhefsTer59	frameshift	Exon 6 of 15	ENSP00000361562.3	X6R8A1
	CTSA	ENST00000191018.9	TSL:1	c.595delC	p.Leu199PhefsTer59	frameshift	Exon 6 of 15	ENSP00000191018.5	P10619-1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Likely pathogenic

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
1	-	-	Combined deficiency of sialidase AND beta galactosidase (1)
1	-	-	Non-immune hydrops fetalis (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		1.8
Mutation Taster		=0/200	disease causing (ClinVar)

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: rs786205670; hg19: chr20-44521512;