3-122337581-CTT-C
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Variant summary
Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1PM2PP5_Moderate
The NM_005213.4(CSTA):c.102_103del(p.Tyr35ArgfsTer9) variant causes a frameshift change. The variant allele was found at a frequency of 0.000000685 in 1,460,752 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★). Variant results in nonsense mediated mRNA decay.
Frequency
Genomes: not found (cov: 32)
Exomes 𝑓: 6.8e-7 ( 0 hom. )
Consequence
CSTA
NM_005213.4 frameshift
NM_005213.4 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 4.85
Genes affected
CSTA (HGNC:2481): (cystatin A) The cystatin superfamily encompasses proteins that contain multiple cystatin-like sequences. Some of the members are active cysteine protease inhibitors, while others have lost or perhaps never acquired this inhibitory activity. There are three inhibitory families in the superfamily, including the type 1 cystatins (stefins), type 2 cystatins, and kininogens. This gene encodes a stefin that functions as a cysteine protease inhibitor, forming tight complexes with papain and the cathepsins B, H, and L. The protein is one of the precursor proteins of cornified cell envelope in keratinocytes and plays a role in epidermal development and maintenance. Stefins have been proposed as prognostic and diagnostic tools for cancer. [provided by RefSeq, Jul 2008]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 12 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 3-122337581-CTT-C is Pathogenic according to our data. Variant chr3-122337581-CTT-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 450304.Status of the report is criteria_provided_single_submitter, 1 stars.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
CSTA | NM_005213.4 | c.102_103del | p.Tyr35ArgfsTer9 | frameshift_variant | 2/3 | ENST00000264474.4 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
CSTA | ENST00000264474.4 | c.102_103del | p.Tyr35ArgfsTer9 | frameshift_variant | 2/3 | 1 | NM_005213.4 | P1 | |
CSTA | ENST00000479204.1 | c.102_103del | p.Tyr35ArgfsTer9 | frameshift_variant | 2/2 | 2 |
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD3 genomes
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GnomAD3 exomes AF: 0.00000398 AC: 1AN: 251336Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 135838
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GnomAD4 exome AF: 6.85e-7 AC: 1AN: 1460752Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 726764
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GnomAD4 genome Cov.: 32
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ClinVar
Significance: Likely pathogenic
Submissions summary: Pathogenic:1
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
not provided Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Jul 06, 2017 | The c.102_103delTT variant in the CSTA gene has not been reported previously as a pathogenic variant nor as a benign variant, to our knowledge. This variant causes a frameshift starting with codon Tyrosine 35, changes this amino acid to an Arginine residue, and creates a premature Stop codon at position 9 of the new reading frame, denoted p.Tyr35ArgfsX9. The c.102_103delTT variant is predicted to cause loss of normal protein function through protein truncation, with the last 64 correct amino acids replaced by 8 incorrect residues. This variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). We interpret c.102_103delTT as a likely pathogenic variant. - |
Computational scores
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Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at