rs886039898

Variant names:

• chr20-45891619-GCTG-C
• rs886039898
• NM_000308.4:c.51_54delGCTGinsC

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP3 BP6

The NM_000308.4(CTSA):​c.51_54delGCTGinsC​(p.Leu18del) variant causes a conservative inframe deletion, synonymous change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency: Genomes: not found (cov: 32)
• Consequence: CTSA NM_000308.4 conservative_inframe_deletion, synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:1
• Conservation: PhyloP100: 4.23
• Publications: 4 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: G2P, Labcorp Genetics (formerly Invitae), Genomics England PanelApp, Orphanet, ClinGen, Illumina

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP3: Nonframeshift variant in repetitive region in NM_000308.4
• BP6: Variant 20-45891619-GCTG-C is Benign according to our data. Variant chr20-45891619-GCTG-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 266025.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CTSA	NM_000308.4	MANE Select	c.51_54delGCTGinsC	p.Leu18del	conservative_inframe_deletion synonymous	Exon 2 of 15	NP_000299.3
	CTSA	NM_001127695.3		c.51_54delGCTGinsC	p.Leu18del	conservative_inframe_deletion synonymous	Exon 2 of 15	NP_001121167.1
	CTSA	NM_001167594.3		c.51_54delGCTGinsC	p.Leu18del	conservative_inframe_deletion synonymous	Exon 2 of 14	NP_001161066.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CTSA	ENST00000646241.3	MANE Select	c.51_54delGCTGinsC	p.Leu18del	conservative_inframe_deletion synonymous	Exon 2 of 15	ENSP00000493613.2
	CTSA	ENST00000372484.8	TSL:1	c.105_108delGCTGinsC	p.Leu36del	conservative_inframe_deletion synonymous	Exon 2 of 15	ENSP00000361562.3
	CTSA	ENST00000191018.9	TSL:1	c.51_54delGCTGinsC	p.Leu18del	conservative_inframe_deletion synonymous	Exon 2 of 15	ENSP00000191018.5

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: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	1	Combined deficiency of sialidase AND beta galactosidase (2)
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		4.2
Mutation Taster		=56/44	polymorphism

Splicing

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

Other links and lift over

dbSNP: rs886039898; hg19: chr20-44520258; COSMIC: COSV51942674; COSMIC: COSV51942674;