rs886039898

Variant names:

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

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 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

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• 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 id is 266025.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=2}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CTSA	NM_000308.4	c.51_54delGCTGinsC	p.Leu18del	conservative_inframe_deletion, synonymous_variant	Exon 2 of 15	ENST00000646241.3	NP_000299.3
CTSA	NM_001127695.3	c.51_54delGCTGinsC	p.Leu18del	conservative_inframe_deletion, synonymous_variant	Exon 2 of 15		NP_001121167.1
CTSA	NM_001167594.3	c.51_54delGCTGinsC	p.Leu18del	conservative_inframe_deletion, synonymous_variant	Exon 2 of 14		NP_001161066.2
CTSA	NR_133656.2	n.96_99delGCTGinsC		non_coding_transcript_exon_variant	Exon 2 of 15

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CTSA	ENST00000646241.3	c.51_54delGCTGinsC	p.Leu18del	conservative_inframe_deletion, synonymous_variant	Exon 2 of 15		NM_000308.4	ENSP00000493613.2

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

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Combined deficiency of sialidase AND beta galactosidase Uncertain:1 Benign:1

Aug 09, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant has been observed in individual(s) with clinical features of galactosialidosis (PMID: 28554332). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This variant, c.105_108delinsC, is a complex sequence change that results in the deletion of 1 amino acid(s) in the CTSA protein (p.Leu37del). ClinVar contains an entry for this variant (Variation ID: 558865). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. -

Sep 14, 2017

HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: research

- -

not provided Uncertain:1

Feb 15, 2022

Mayo Clinic Laboratories, Mayo Clinic

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PM2 -

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