rs137854547

Positions:

• chr20-45898065-G-A

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_000308.4(CTSA):​c.1315G>A​(p.Gly439Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000821 in 1,461,886 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000082 (0 hom.)
• Consequence: CTSA NM_000308.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2 U:1
• Conservation: PhyloP100: 9.59

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]

ACMG classification

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.969

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CTSA	NM_000308.4	c.1315G>A	p.Gly439Ser	missense_variant	14/15	ENST00000646241.3	NP_000299.3
CTSA	NM_001127695.3	c.1315G>A	p.Gly439Ser	missense_variant	14/15		NP_001121167.1
CTSA	NM_001167594.3	c.1264G>A	p.Gly422Ser	missense_variant	13/14		NP_001161066.2
CTSA	NR_133656.2	n.1367G>A		non_coding_transcript_exon_variant	14/15

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CTSA	ENST00000646241.3	c.1315G>A	p.Gly439Ser	missense_variant	14/15		NM_000308.4	ENSP00000493613

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.0000119 AC: 3 AN: 251436 Hom.: 0 AF XY: 0.0000147 AC XY: 2 AN XY: 135896

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000176

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000821 AC: 12 AN: 1461886 Hom.: 0 Cov.: 31 AF XY: 0.00000963 AC XY: 7 AN XY: 727248

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: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000809

Gnomad4 OTH exome AF: 0.0000331

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000557 Hom.: 0

Bravo AF: 0.0000113

ExAC AF: 0.00000824 AC: 1

EpiCase AF: 0.000109

EpiControl AF: 0.0000593

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:2 Uncertain:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Combined deficiency of sialidase AND beta galactosidase Pathogenic:1 Uncertain:1

Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Nov 24, 2023	This sequence change replaces glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 457 of the CTSA protein (p.Gly457Ser). This variant is present in population databases (rs137854547, gnomAD 0.003%). This missense change has been observed in individual(s) with galactosialidosis (PMID: 8968752). ClinVar contains an entry for this variant (Variation ID: 385). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt CTSA protein function with a positive predictive value of 80%. Experimental studies have shown that this missense change affects CTSA function (PMID: 8968752). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Oct 08, 2024	Variant summary: CTSA c.1315G>A (p.Gly439Ser) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 1.2e-05 in 251436 control chromosomes. c.1315G>A has been reported in the literature in an individual affected with autosomal recessive Galactosialidosis with the second allele change not being detected (Zhou_1996). These report(s) do not provide unequivocal conclusions about association of the variant with Galactosialidosis. At least one publication reports experimental evidence evaluating an impact on protein function in patient-derived fibroblasts. The most pronounced variant effect results in a total loss of enzymatic activity due to attenuated phosphorylation and lysosomal localization and maturation of the mutant precursor (Zhou_1996). ClinVar contains an entry for this variant (Variation ID: 385). Based on the evidence outlined above, the variant was classified as likely pathogenic. -

Galactosialidosis, early infantile Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Dec 01, 1991

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.90
BayesDel_addAF	Pathogenic	0.52	D
BayesDel_noAF	Pathogenic	0.60
CADD	Uncertain	26
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.84	D;.;D;D;D
Eigen	Pathogenic	1.0
Eigen_PC	Pathogenic	0.91
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.96	D;D;.;.;D
M_CAP	Pathogenic	0.81	D
MetaRNN	Pathogenic	0.97	D;D;D;D;D
MetaSVM	Pathogenic	0.97	D
MutationAssessor	Pathogenic	4.0	.;.;H;H;H
MutationTaster	Benign	1.0	A;A;A
PrimateAI	Uncertain	0.64	T
PROVEAN	Pathogenic	-5.8	D;D;.;D;.
REVEL	Pathogenic	0.99
Sift	Pathogenic	0.0	D;D;.;D;.
Sift4G	Pathogenic	0.0	D;D;.;D;D
Polyphen		1.0	.;.;D;D;D
Vest4		0.97
MVP		0.99
MPC		1.2
ClinPred		1.0	D
GERP RS		5.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.98
gMVP		0.89

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: rs137854547; hg19: chr20-44526704; COSMIC: COSV99509770; COSMIC: COSV99509770;