rs875989777

Variant summary

Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong

The NM_000308.4(CTSA):​c.833_834delAT​(p.Tyr278CysfsTer12) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,886 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: not found (cov: 32)
Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

CTSA
NM_000308.4 frameshift

Scores

Not classified

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:3

Conservation

PhyloP100: 7.46

Publications

2 publications found
Variant links:
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

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 18 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 20-45894703-CTA-C is Pathogenic according to our data. Variant chr20-45894703-CTA-C is described in ClinVar as [Pathogenic]. Clinvar id is 225877.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
CTSANM_000308.4 linkc.833_834delAT p.Tyr278CysfsTer12 frameshift_variant Exon 9 of 15 ENST00000646241.3 NP_000299.3 P10619-1X6R8A1
CTSANM_001127695.3 linkc.833_834delAT p.Tyr278CysfsTer12 frameshift_variant Exon 9 of 15 NP_001121167.1 P10619-1
CTSANM_001167594.3 linkc.782_783delAT p.Tyr261CysfsTer12 frameshift_variant Exon 8 of 14 NP_001161066.2 P10619-2B4E324X6R5C5
CTSANR_133656.2 linkn.885_886delAT non_coding_transcript_exon_variant Exon 9 of 15

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
CTSAENST00000646241.3 linkc.833_834delAT p.Tyr278CysfsTer12 frameshift_variant Exon 9 of 15 NM_000308.4 ENSP00000493613.2 P10619-1

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
AF:
6.84e-7
AC:
1
AN:
1461886
Hom.:
0
AF XY:
0.00
AC XY:
0
AN XY:
727246
show subpopulations
African (AFR)
AF:
0.00
AC:
0
AN:
33480
American (AMR)
AF:
0.00
AC:
0
AN:
44724
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
26136
East Asian (EAS)
AF:
0.00
AC:
0
AN:
39700
South Asian (SAS)
AF:
0.00
AC:
0
AN:
86254
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
53420
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
5768
European-Non Finnish (NFE)
AF:
8.99e-7
AC:
1
AN:
1112008
Other (OTH)
AF:
0.00
AC:
0
AN:
60396
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.525
Heterozygous variant carriers
0
0
1
1
2
2
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Exome Het
Variant carriers
0
2
4
6
8
10
<30
30-35
35-40
40-45
45-50
50-55
55-60
60-65
65-70
70-75
75-80
>80
Age
GnomAD4 genome
Cov.:
32

ClinVar

Significance: Pathogenic
Submissions summary: Pathogenic:3
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Combined deficiency of sialidase AND beta galactosidase Pathogenic:3
Dec 22, 2022
Labcorp Genetics (formerly Invitae), Labcorp
Significance:Pathogenic
Review Status:criteria provided, single submitter
Collection Method:clinical testing

This sequence change creates a premature translational stop signal (p.Tyr296Cysfs*12) in the CTSA gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in CTSA are known to be pathogenic (PMID: 15110321, 23915561). For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 225877). This premature translational stop signal has been observed in individual(s) with clinical features of galactosialidosis (PMID: 24769197). This variant is not present in population databases (gnomAD no frequency). -

Jul 01, 2014
Lupski Lab, Baylor-Hopkins CMG, Baylor College of Medicine
Significance:Pathogenic
Review Status:criteria provided, single submitter
Collection Method:research

- -

Jun 05, 2024
Fulgent Genetics, Fulgent Genetics
Significance:Pathogenic
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
PhyloP100
7.5
Mutation Taster
=0/200
disease causing (ClinVar)

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.010
Details are displayed if max score is > 0.2

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

Publications

Other links and lift over

dbSNP: rs875989777; hg19: chr20-44523342; API