rs769812697

Variant names:

• chr20-45892794-CTT-C
• rs769812697
• NM_000308.4:c.517_518delTT

Your query was ambiguous. Multiple possible variants found:

• chr20-45892794-CTT-C
• chr20-45892794-CTT-CT

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_000308.4(CTSA):​c.517_518delTT​(p.Phe173ProfsTer39) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000372 in 1,614,096 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: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000034 (0 hom.)
• Consequence: CTSA NM_000308.4 frameshift
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:4
• Conservation: PhyloP100: 7.98

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]

ENSG00000271984 (HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 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 20-45892794-CTT-C is Pathogenic according to our data. Variant chr20-45892794-CTT-C is described in ClinVar as [Pathogenic]. Clinvar id is 387.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
CTSA	NM_000308.4	c.517_518delTT	p.Phe173ProfsTer39	frameshift_variant	Exon 6 of 15	ENST00000646241.3	NP_000299.3
CTSA	NM_001127695.3	c.517_518delTT	p.Phe173ProfsTer39	frameshift_variant	Exon 6 of 15		NP_001121167.1
CTSA	NM_001167594.3	c.466_467delTT	p.Phe156ProfsTer39	frameshift_variant	Exon 5 of 14		NP_001161066.2
CTSA	NR_133656.2	n.562_563delTT		non_coding_transcript_exon_variant	Exon 6 of 15

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CTSA	ENST00000646241.3	c.517_518delTT	p.Phe173ProfsTer39	frameshift_variant	Exon 6 of 15		NM_000308.4	ENSP00000493613.2

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152214 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000342 AC: 5 AN: 1461882 Hom.: 0 AF XY: 0.00000413 AC XY: 3 AN XY: 727246

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000450

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152214 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74364

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00

Bravo AF: 0.00000378

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Combined deficiency of sialidase AND beta galactosidase Pathogenic:3

Apr 04, 2017

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.Phe191ProfsX39 variant in CTSA has been reported in 1 individual (compound heterozygous) with clinical features of galactosialidosis-late infantile type (Richard 1998) and was absent from large population studies. However, these types of assays may not accurately represent biological function. This variant is predicted to cause a frameshift, which alters the protein’s amino acid sequence beginning at position 191 and leads to a premature termination codon 39 amino acids downstream. This alteration is then predicted to lead to a truncated or absent protein. In vitro functional studies support that the p.Phe191ProfsX39 variant impacts protein function (Richard 1998). In summary, this variant meets criteria to be classified as pathogenic for galactosialidosis in an autosomal recessive manner based upon case studies, absence from controls and functional evidence. -

Apr 06, 2023

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: CTSA c.517_518delTT/p.Phe173ProfsX39 (also known as c.569_570delTT) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory. The variant was absent in 251484 control chromosomes. c.517_518delTT has been reported in the literature in individuals affected with Galactosialidosis (e.g. Richard_1998, Okulu_2017). These data indicate that the variant may be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in <10% of normal activity (Richard_1998). 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 pathogenic. -

Apr 08, 2024

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.Phe191Profs*39) 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). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with galactosialidosis (PMID: 9603439). This variant is also known as c517delTT. ClinVar contains an entry for this variant (Variation ID: 387). For these reasons, this variant has been classified as Pathogenic. -

Galactosialidosis, late infantile Pathogenic:1

Jan 01, 1998

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs769812697; hg19: chr20-44521433;