20-45893314-A-G

Position:

• chr20-45893314-A-G

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM2 PP3 PP5_Very_Strong

The NM_000308.4(CTSA):​c.692+3A>G variant causes a splice donor region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000548 in 1,458,546 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000055 (0 hom.)
• Consequence: CTSA NM_000308.4 splice_donor_region, intron
• Scores: Splicing: ADA: 0.9953
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 3.01

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]

(HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 11 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF, max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
• PP5: Variant 20-45893314-A-G is Pathogenic according to our data. Variant chr20-45893314-A-G is described in ClinVar as [Pathogenic]. Clinvar id is 376.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CTSA	NM_000308.4	c.692+3A>G		splice_donor_region_variant, intron_variant		ENST00000646241.3	NP_000299.3
CTSA	NM_001127695.3	c.692+3A>G		splice_donor_region_variant, intron_variant			NP_001121167.1
CTSA	NM_001167594.3	c.641+3A>G		splice_donor_region_variant, intron_variant			NP_001161066.2
CTSA	NR_133656.2	n.744+3A>G		splice_donor_region_variant, intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CTSA	ENST00000646241.3	c.692+3A>G		splice_donor_region_variant, intron_variant			NM_000308.4	ENSP00000493613
	ENST00000607703.1	n.106T>C		non_coding_transcript_exon_variant	1/2	4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000548 AC: 8 AN: 1458546 Hom.: 0 Cov.: 31 AF XY: 0.00000689 AC XY: 5 AN XY: 725902

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000202

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Asia WGS AF: 0.000289 AC: 1 AN: 3478

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:2

Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jun 04, 2023	For these reasons, this variant has been classified as Pathogenic. Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. ClinVar contains an entry for this variant (Variation ID: 376). This variant is also known as IVS7+3A>G. This variant has been observed in individual(s) with galactosialidosis (PMID: 31044084, 32774297). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is not present in population databases (gnomAD no frequency). This sequence change falls in intron 7 of the CTSA gene. It does not directly change the encoded amino acid sequence of the CTSA protein. It affects a nucleotide within the consensus splice site. -
Pathogenic, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	The CTSA c.746+3A>G variant, also known as the SpDEx7 variant, has been reported in six studies in which it is found in a total of 14 individuals with galactosialidosis, all of Japanese origin, including nine in a homozygous state and five in a compound heterozygous state (Shimmoto et al. 1990; Shimmoto et al. 1993; Zhou et al. 1993; Tatano et al. 2006; Yamazaki et al. 2014; Hossain et al. 2016). Control data are unavailable for this variant which is also not found in the 1000 Genomes Project, the Exome Sequencing Project, or the Exome Aggregation Consortium. Functional studies by Shimmoto et al. (1993) have demonstrated that the variant causes aberrant splicing and skipping of exon 7 while allowing the production of a small amount of correctly spliced mRNA. This is thought to result in the milder late-onset phenotype seen in individuals who are homozygous for the variant while a more severe phenotype is seen in individuals who are compound heterozygotes for this variant in combination with different missense variants. Reduced capthepsin activity (one percent of normal levels) was demonstrated in an individual who was a compound heterozygote for the variant (Zhou et al. 1993). Based on the evidence, the c.746+3A>G variant is classified as pathogenic for galactosialidosis. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. -

Galactosialidosis, adult Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Jun 25, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.41
CADD	Benign	21
DANN	Benign	0.91

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.83
SpliceAI score (max)		0.61		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.61		Position offset: -3

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

Publications

LitVar

Other links and lift over

dbSNP: rs786200859; hg19: chr20-44521953;