rs786200859

Variant names:

• chr20-45893314-A-G
• rs786200859
• NM_000308.4:c.692+3A>G

Variant summary

Our verdict is Likely pathogenic. The variant received 9 ACMG points: 9P and 0B. PP3 PP5_Very_Strong

The NM_000308.4(CTSA):​c.692+3A>G variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000548 in 1,458,546 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (★★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000055 (0 hom.)
• Consequence: CTSA NM_000308.4 splice_region, intron
• Scores: Splicing: ADA: 0.9953
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 3.01
• Publications: 5 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

ENSG00000271984 (HGNC:):

ACMG classification

Our verdict: Likely_pathogenic. The variant received 9 ACMG points.

• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF, max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
• PP5: Variant 20-45893314-A-G is Pathogenic according to our data. Variant chr20-45893314-A-G is described in ClinVar as Pathogenic. ClinVar VariationId is 376.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CTSA	NM_000308.4	c.692+3A>G		splice_region_variant, intron_variant	Intron 7 of 14	ENST00000646241.3	NP_000299.3
CTSA	NM_001127695.3	c.692+3A>G		splice_region_variant, intron_variant	Intron 7 of 14		NP_001121167.1
CTSA	NM_001167594.3	c.641+3A>G		splice_region_variant, intron_variant	Intron 6 of 13		NP_001161066.2
CTSA	NR_133656.2	n.744+3A>G		splice_region_variant, intron_variant	Intron 7 of 14

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CTSA	ENST00000646241.3	c.692+3A>G		splice_region_variant, intron_variant	Intron 7 of 14		NM_000308.4	ENSP00000493613.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000548 AC: 8 AN: 1458546 Hom.: 0 Cov.: 31 AF XY: 0.00000689 AC XY: 5 AN XY: 725902

African (AFR) AF: 0.00 AC: 0 AN: 33396

American (AMR) AF: 0.00 AC: 0 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26116

East Asian (EAS) AF: 0.000202 AC: 8 AN: 39676

South Asian (SAS) AF: 0.00 AC: 0 AN: 86192

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53412

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5758

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1108998

Other (OTH) AF: 0.00 AC: 0 AN: 60276

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Combined deficiency of sialidase AND beta galactosidase Pathogenic:2

Feb 23, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change falls in intron 7 of the CTSA gene. It does not directly change the encoded amino acid sequence of the CTSA protein. It affects a nucleotide within the consensus splice site. This variant is not present in population databases (gnomAD no frequency). This variant has been observed in individual(s) with galactosialidosis (PMID: 31044084, 32774297). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is also known as IVS7+3A>G. ClinVar contains an entry for this variant (Variation ID: 376). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. -

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The CTSA c.746+3A>G variant, also known as the SpDEx7 variant, has been reported in six studies in which it is found in a total of 14 individuals with galactosialidosis, all of Japanese origin, including nine in a homozygous state and five in a compound heterozygous state (Shimmoto et al. 1990; Shimmoto et al. 1993; Zhou et al. 1993; Tatano et al. 2006; Yamazaki et al. 2014; Hossain et al. 2016). Control data are unavailable for this variant which is also not found in the 1000 Genomes Project, the Exome Sequencing Project, or the Exome Aggregation Consortium. Functional studies by Shimmoto et al. (1993) have demonstrated that the variant causes aberrant splicing and skipping of exon 7 while allowing the production of a small amount of correctly spliced mRNA. This is thought to result in the milder late-onset phenotype seen in individuals who are homozygous for the variant while a more severe phenotype is seen in individuals who are compound heterozygotes for this variant in combination with different missense variants. Reduced capthepsin activity (one percent of normal levels) was demonstrated in an individual who was a compound heterozygote for the variant (Zhou et al. 1993). Based on the evidence, the c.746+3A>G variant is classified as pathogenic for galactosialidosis. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. -

Galactosialidosis, adult Pathogenic:1

Jun 25, 2021

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.41
CADD	Benign	21
DANN	Benign	0.91
PhyloP100		3.0
Mutation Taster		=1/99	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.83
SpliceAI score (max)		0.61		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.61		Position offset: -3

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

Other links and lift over

dbSNP: rs786200859; hg19: chr20-44521953;