rs875989777

Variant names:

• chr20-45894703-CTA-C
• rs875989777
• NM_000308.4:c.833_834delAT

Variant summary

Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_000308.4(CTSA):​c.833_834delAT​(p.Tyr278CysfsTer12) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,886 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: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: CTSA NM_000308.4 frameshift
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 7.46
• Publications: 2 publications found

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]

CTSA Gene-Disease associations (from GenCC):

• galactosialidosis

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: G2P, Labcorp Genetics (formerly Invitae), Genomics England PanelApp, Orphanet, ClinGen, Illumina

ACMG classification

Our verdict: Pathogenic. The variant received 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 20-45894703-CTA-C is Pathogenic according to our data. Variant chr20-45894703-CTA-C is described in ClinVar as [Pathogenic]. Clinvar id is 225877.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.833_834delAT	p.Tyr278CysfsTer12	frameshift_variant	Exon 9 of 15	ENST00000646241.3	NP_000299.3
CTSA	NM_001127695.3	c.833_834delAT	p.Tyr278CysfsTer12	frameshift_variant	Exon 9 of 15		NP_001121167.1
CTSA	NM_001167594.3	c.782_783delAT	p.Tyr261CysfsTer12	frameshift_variant	Exon 8 of 14		NP_001161066.2
CTSA	NR_133656.2	n.885_886delAT		non_coding_transcript_exon_variant	Exon 9 of 15

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CTSA	ENST00000646241.3	c.833_834delAT	p.Tyr278CysfsTer12	frameshift_variant	Exon 9 of 15		NM_000308.4	ENSP00000493613.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461886 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 727246

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86254

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1112008

Other (OTH) AF: 0.00 AC: 0 AN: 60396

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Combined deficiency of sialidase AND beta galactosidase Pathogenic:3

Dec 22, 2022

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.Tyr296Cysfs*12) 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). For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 225877). This premature translational stop signal has been observed in individual(s) with clinical features of galactosialidosis (PMID: 24769197). This variant is not present in population databases (gnomAD no frequency). -

Jul 01, 2014

Lupski Lab, Baylor-Hopkins CMG, Baylor College of Medicine

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

- -

Jun 05, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		7.5
Mutation Taster		=0/200	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs875989777; hg19: chr20-44523342;