rs137854540
Variant summary
Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM2PP3_StrongPP5_Moderate
The NM_000308.4(CTSA):c.1318T>G(p.Phe440Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000496 in 1,613,876 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 Likely pathogenic (★). Synonymous variant affecting the same amino acid position (i.e. F440F) has been classified as Likely benign.
Frequency
Consequence
NM_000308.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_pathogenic. Variant got 8 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
CTSA | NM_000308.4 | c.1318T>G | p.Phe440Val | missense_variant | 14/15 | ENST00000646241.3 | |
CTSA | NM_001127695.3 | c.1318T>G | p.Phe440Val | missense_variant | 14/15 | ||
CTSA | NM_001167594.3 | c.1267T>G | p.Phe423Val | missense_variant | 13/14 | ||
CTSA | NR_133656.2 | n.1370T>G | non_coding_transcript_exon_variant | 14/15 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
CTSA | ENST00000646241.3 | c.1318T>G | p.Phe440Val | missense_variant | 14/15 | NM_000308.4 |
Frequencies
GnomAD3 genomes ? AF: 0.0000197 AC: 3AN: 151994Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.00000795 AC: 2AN: 251430Hom.: 0 AF XY: 0.0000147 AC XY: 2AN XY: 135898
GnomAD4 exome AF: 0.00000342 AC: 5AN: 1461882Hom.: 0 Cov.: 31 AF XY: 0.00000550 AC XY: 4AN XY: 727246
GnomAD4 genome ? AF: 0.0000197 AC: 3AN: 151994Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2AN XY: 74216
ClinVar
Submissions by phenotype
Combined deficiency of sialidase AND beta galactosidase Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Invitae | Dec 05, 2023 | This sequence change replaces phenylalanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 458 of the CTSA protein (p.Phe458Val). This variant is present in population databases (rs137854540, gnomAD 0.004%). This missense change has been observed in individuals with galactosialidosis (PMID: 1756715, 8968752). This variant is also known as p.Phe412Val. ClinVar contains an entry for this variant (Variation ID: 375). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. Experimental studies have shown that this missense change affects CTSA function (PMID: 1756715). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. - |
Galactosialidosis, late infantile Pathogenic:1
Pathogenic, no assertion criteria provided | literature only | OMIM | Dec 01, 1996 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at