20-45891598-CCTGCTGCTGCTGCTGCTGCTGCTGCT-CCTGCTGCTGCTGCTGCTGCTGCTGCTGCT
Variant summary
Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP6_Very_StrongBS1BS2
The NM_000308.4(CTSA):c.54_56dup(p.Leu18dup) variant causes a inframe insertion change involving the alteration of a non-conserved nucleotide. Variant has been reported in ClinVar as Likely benign (★★).
Frequency
Genomes: 𝑓 0.0046 ( 1 hom., cov: 0)
Exomes 𝑓: 0.0059 ( 7 hom. )
Consequence
CTSA
NM_000308.4 inframe_insertion
NM_000308.4 inframe_insertion
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 2.48
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 Benign. Variant got -16 ACMG points.
BP6
?
Variant 20-45891598-C-CCTG is Benign according to our data. Variant chr20-45891598-C-CCTG is described in ClinVar as [Likely_benign]. Clinvar id is 632780.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
BS1
?
Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00464 (696/149906) while in subpopulation NFE AF= 0.00777 (526/67714). AF 95% confidence interval is 0.00722. There are 1 homozygotes in gnomad4. There are 303 alleles in male gnomad4 subpopulation. Median coverage is 0. This position pass quality control queck.
BS2
?
High Homozygotes in GnomAdExome4 at 7 AR gene
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
CTSA | NM_000308.4 | c.54_56dup | p.Leu18dup | inframe_insertion | 2/15 | ENST00000646241.3 | |
CTSA | NM_001127695.3 | c.54_56dup | p.Leu18dup | inframe_insertion | 2/15 | ||
CTSA | NM_001167594.3 | c.54_56dup | p.Leu18dup | inframe_insertion | 2/14 | ||
CTSA | NR_133656.2 | n.99_101dup | non_coding_transcript_exon_variant | 2/15 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
CTSA | ENST00000646241.3 | c.54_56dup | p.Leu18dup | inframe_insertion | 2/15 | NM_000308.4 |
Frequencies
GnomAD3 genomes ? AF: 0.00465 AC: 696AN: 149792Hom.: 1 Cov.: 0
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GnomAD3 exomes AF: 0.00573 AC: 1167AN: 203638Hom.: 5 AF XY: 0.00565 AC XY: 637AN XY: 112766
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GnomAD4 exome AF: 0.00585 AC: 8382AN: 1432024Hom.: 7 Cov.: 0 AF XY: 0.00571 AC XY: 4068AN XY: 712836
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GnomAD4 genome ? AF: 0.00464 AC: 696AN: 149906Hom.: 1 Cov.: 0 AF XY: 0.00415 AC XY: 303AN XY: 73070
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ClinVar
Significance: Benign/Likely benign
Submissions summary: Benign:4
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not specified Benign:1
Benign, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Jun 15, 2018 | Variant summary: CTSA c.108_110dupGCT (p.Leu37dup) results in an in-frame insertion of a leucine into a repetitive region of the encoded protein sequence; this region consists of several consecutive leucines and doesn't have a known function. The variant allele was found at a frequency of 0.0055 in 230752 control chromosomes in the gnomAD database, including 5 homozygotes. The observed variant frequency is approximately 3.46 fold of the estimated maximal expected allele frequency for a pathogenic variant in CTSA causing Galactosialidosis phenotype (0.0016), strongly suggesting that the variant is benign. To our knowledge, no occurrence of c.108_110dupGCT in individuals affected with Galactosialidosis and no experimental evidence demonstrating its impact on protein function have been reported. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as benign. - |
CTSA-related disorder Benign:1
Benign, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Apr 15, 2019 | This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). - |
not provided Benign:1
Likely benign, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Mar 01, 2024 | CTSA: BS2 - |
Combined deficiency of sialidase AND beta galactosidase Benign:1
Benign, criteria provided, single submitter | clinical testing | Invitae | Jan 31, 2024 | - - |
Computational scores
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Find out detailed SpliceAI scores and Pangolin per-transcript scores at