rs137854547
Variant summary
Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2PP3_Strong
The NM_000308.4(CTSA):c.1315G>A(p.Gly439Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000821 in 1,461,886 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).
Frequency
Genomes: not found (cov: 32)
Exomes 𝑓: 0.0000082 ( 0 hom. )
Consequence
CTSA
NM_000308.4 missense
NM_000308.4 missense
Scores
14
3
1
Clinical Significance
Conservation
PhyloP100: 9.59
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]
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ACMG classification
Classification made for transcript
Verdict is Likely_pathogenic. Variant got 6 ACMG points.
PM2
?
Very rare variant in population databases, with high coverage;
PP3
?
MetaRNN computational evidence supports a deleterious effect, 0.969
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
CTSA | NM_000308.4 | c.1315G>A | p.Gly439Ser | missense_variant | 14/15 | ENST00000646241.3 | |
CTSA | NM_001127695.3 | c.1315G>A | p.Gly439Ser | missense_variant | 14/15 | ||
CTSA | NM_001167594.3 | c.1264G>A | p.Gly422Ser | missense_variant | 13/14 | ||
CTSA | NR_133656.2 | n.1367G>A | non_coding_transcript_exon_variant | 14/15 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
CTSA | ENST00000646241.3 | c.1315G>A | p.Gly439Ser | missense_variant | 14/15 | NM_000308.4 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD3 genomes
?
Cov.:
32
GnomAD3 exomes AF: 0.0000119 AC: 3AN: 251436Hom.: 0 AF XY: 0.0000147 AC XY: 2AN XY: 135896
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GnomAD4 exome AF: 0.00000821 AC: 12AN: 1461886Hom.: 0 Cov.: 31 AF XY: 0.00000963 AC XY: 7AN XY: 727248
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GnomAD4 genome ? Cov.: 32
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?
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32
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ClinVar
Significance: Uncertain significance
Submissions summary: Pathogenic:1Uncertain:1
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
Galactosialidosis, early infantile Pathogenic:1
Pathogenic, no assertion criteria provided | literature only | OMIM | Dec 01, 1991 | - - |
Combined deficiency of sialidase AND beta galactosidase Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Nov 24, 2023 | This sequence change replaces glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 457 of the CTSA protein (p.Gly457Ser). This variant is present in population databases (rs137854547, gnomAD 0.003%). This missense change has been observed in individual(s) with galactosialidosis (PMID: 8968752). ClinVar contains an entry for this variant (Variation ID: 385). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt CTSA protein function with a positive predictive value of 80%. Experimental studies have shown that this missense change affects CTSA function (PMID: 8968752). 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. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
Cadd
Uncertain
Dann
Uncertain
DEOGEN2
Pathogenic
D;.;D;D;D
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Pathogenic
D
LIST_S2
Uncertain
D;D;.;.;D
M_CAP
Pathogenic
D
MetaRNN
Pathogenic
D;D;D;D;D
MetaSVM
Pathogenic
D
MutationTaster
Benign
A;A;A
PrimateAI
Uncertain
T
PROVEAN
Pathogenic
D;D;.;D;.
REVEL
Pathogenic
Sift
Pathogenic
D;D;.;D;.
Sift4G
Pathogenic
D;D;.;D;D
Polyphen
1.0
.;.;D;D;D
Vest4
MVP
MPC
ClinPred
D
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
Varity_R
gMVP
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at