rs137854542

Positions:

• chr20-45891990-C-T

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM2 PP3_Strong PP5_Moderate

The NM_000308.4(CTSA):​c.269C>T​(p.Ser90Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 12/21 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: CTSA NM_000308.4 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 7.80

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 8 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.992
• PP5: Variant 20-45891990-C-T is Pathogenic according to our data. Variant chr20-45891990-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 379.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CTSA	NM_000308.4	c.269C>T	p.Ser90Leu	missense_variant	3/15	ENST00000646241.3	NP_000299.3
CTSA	NM_001127695.3	c.269C>T	p.Ser90Leu	missense_variant	3/15		NP_001121167.1
CTSA	NM_001167594.3	c.269C>T	p.Ser90Leu	missense_variant	3/14		NP_001161066.2
CTSA	NR_133656.2	n.314C>T		non_coding_transcript_exon_variant	3/15

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CTSA	ENST00000646241.3	c.269C>T	p.Ser90Leu	missense_variant	3/15		NM_000308.4	ENSP00000493613

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

Submissions by phenotype

Combined deficiency of sialidase AND beta galactosidase Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	Molecular Genetics Department, Kulakov National Medical Research Center for Obstetrics, Gynecology and Perinatology	-	A previously undescribed nucleotide variant creates a missense p.Ser90Leu in the CTSA gene. The variant was observed in compound heterozygous state with a LoF variant in an individual affected with hydrops fetalis and ventriculomegaly. Homozygous and compound heterozygous variants are reported in patients with Galactosialidosis, 256540. Another nucleotide variant causing same missense (c.268_269TC>CT) was previously reported in compound heterozygous state in patient with galactosialidosis [Shimmoto et al., 1993, PMID: 8514852]. Pathogenicity prediction algorithms qualify it as pathogenic (PolyPhen-2: 1.0; Sift: 0.0). The variant is not present in population database (gnomAD no frequency). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as likely pathogenic. -
Pathogenic, no assertion criteria provided	literature only	OMIM	Jun 01, 1993	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.97
BayesDel_addAF	Pathogenic	0.54	D
BayesDel_noAF	Pathogenic	0.54
CADD	Pathogenic	32
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.85	D;.;D;D;D;D
Eigen	Pathogenic	1.1
Eigen_PC	Pathogenic	0.96
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	1.0	D;D;.;.;D;D
M_CAP	Pathogenic	0.57	D
MetaRNN	Pathogenic	0.99	D;D;D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	4.9	.;.;H;H;.;H
MutationTaster	Benign	1.0	A;A;A
PrimateAI	Uncertain	0.61	T
PROVEAN	Pathogenic	-5.7	D;D;.;D;.;D
REVEL	Pathogenic	0.97
Sift	Uncertain	0.0020	D;D;.;D;.;D
Sift4G	Uncertain	0.0020	D;D;.;D;D;D
Polyphen		1.0	.;.;D;D;.;D
Vest4		0.94
MutPred		0.96		.;.;Loss of disorder (P = 0.0097);Loss of disorder (P = 0.0097);Loss of disorder (P = 0.0097);Loss of disorder (P = 0.0097);
MVP		0.99
MPC		1.1
ClinPred		1.0	D
GERP RS		5.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.96
gMVP		0.91

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: rs137854542; hg19: chr20-44520629;