rs28934603

Positions:

• chr20-45891761-T-C

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PM1 PM2 PP3_Strong PP5

The NM_000308.4(CTSA):​c.193T>C​(p.Trp65Arg) variant causes a missense, splice region 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. 2/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Pathogenic (no stars).

• Frequency: Genomes: not found (cov: 32)
• Consequence: CTSA NM_000308.4 missense, splice_region
• Scores: Splicing: ADA: 0.8157
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 7.62

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 9 ACMG points.

• PM1: In a chain Lysosomal protective protein 32 kDa chain (size 297) in uniprot entity PPGB_HUMAN there are 10 pathogenic changes around while only 3 benign (77%) in NM_000308.4
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.993
• PP5: Variant 20-45891761-T-C is Pathogenic according to our data. Variant chr20-45891761-T-C is described in ClinVar as [Pathogenic]. Clinvar id is 378.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CTSA	NM_000308.4	c.193T>C	p.Trp65Arg	missense_variant, splice_region_variant	2/15	ENST00000646241.3
CTSA	NM_001127695.3	c.193T>C	p.Trp65Arg	missense_variant, splice_region_variant	2/15
CTSA	NM_001167594.3	c.193T>C	p.Trp65Arg	missense_variant, splice_region_variant	2/14
CTSA	NR_133656.2	n.238T>C		splice_region_variant, non_coding_transcript_exon_variant	2/15

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CTSA	ENST00000646241.3	c.193T>C	p.Trp65Arg	missense_variant, splice_region_variant	2/15		NM_000308.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 35

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Combined deficiency of sialidase AND beta galactosidase Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Jun 01, 1993

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.48	D
BayesDel_noAF	Pathogenic	0.45
CADD	Pathogenic	34
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.84	D;.;D;D;D;D
Eigen	Pathogenic	0.95
Eigen_PC	Pathogenic	0.86
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.95	D;D;.;.;D;D
M_CAP	Pathogenic	0.64	D
MetaRNN	Pathogenic	0.99	D;D;D;D;D;D
MetaSVM	Pathogenic	0.98	D
MutationAssessor	Pathogenic	3.8	.;.;H;H;.;H
MutationTaster	Benign	1.0	A;A;A
PrimateAI	Uncertain	0.78	T
PROVEAN	Pathogenic	-13	D;D;.;D;.;D
REVEL	Pathogenic	0.93
Sift	Uncertain	0.0020	D;D;.;D;.;D
Sift4G	Uncertain	0.0020	D;D;.;D;D;D
Polyphen		1.0	.;.;D;D;.;D
Vest4		0.93
MutPred		0.96		.;.;Gain of disorder (P = 0.0047);Gain of disorder (P = 0.0047);Gain of disorder (P = 0.0047);Gain of disorder (P = 0.0047);
MVP		1.0
MPC		1.6
ClinPred		1.0	D
GERP RS		5.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.98
gMVP		0.94

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.82
dbscSNV1_RF	Pathogenic	0.84
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: rs28934603; hg19: chr20-44520400;