rs137854544

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM1PM2PP5_Very_Strong

The NM_000308.4(CTSA):c.745T>A(p.Tyr249Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000459 in 1,613,036 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★).

Frequency

Genomes: 𝑓 0.000059 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000044 ( 0 hom. )

Consequence

CTSA
NM_000308.4 missense

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:5

Conservation

PhyloP100: 1.74

Variant links:

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 12 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;

PP5

Variant 20-45894040-T-A is Pathogenic according to our data. Variant chr20-45894040-T-A is described in ClinVar as [Pathogenic]. Clinvar id is 381.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
CTSA	NM_000308.4 linkuse as main transcript	c.745T>A	p.Tyr249Asn	missense_variant	8/15	ENST00000646241.3
CTSA	NM_001127695.3 linkuse as main transcript	c.745T>A	p.Tyr249Asn	missense_variant	8/15
CTSA	NM_001167594.3 linkuse as main transcript	c.694T>A	p.Tyr232Asn	missense_variant	7/14
CTSA	NR_133656.2 linkuse as main transcript	n.797T>A		non_coding_transcript_exon_variant	8/15

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CTSA	ENST00000646241.3 linkuse as main transcript	c.745T>A	p.Tyr249Asn	missense_variant	8/15		NM_000308.4		P10619-1

Frequencies

GnomAD3 genomes

AF:

0.0000591

AC:

AN:

152220

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000132

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000358

AC:

AN:

251316

Hom.:

AF XY:

0.0000442

AC XY:

AN XY:

135862

show subpopulations

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:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000791

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000445

AC:

AN:

1460816

Hom.:

Cov.:

AF XY:

0.0000427

AC XY:

AN XY:

726796

show subpopulations

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:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000558

Gnomad4 OTH exome

AF:

0.0000497

GnomAD4 genome

AF:

0.0000591

AC:

AN:

152220

Hom.:

Cov.:

AF XY:

0.0000538

AC XY:

AN XY:

74370

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000132

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000378

ExAC

AF:

0.00000824

AC:

EpiCase

AF:

0.00

EpiControl

AF:

0.0000593

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Combined deficiency of sialidase AND beta galactosidase

Pathogenic:4

Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Dec 27, 2023	This sequence change replaces tyrosine, which is neutral and polar, with asparagine, which is neutral and polar, at codon 267 of the CTSA protein (p.Tyr267Asn). This variant is present in population databases (rs137854544, gnomAD 0.008%). This missense change has been observed in individual(s) with galactosialidosis (PMID: 8514852, 8968752, 22386972, 24769197; Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 381). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant¬†is likely to be tolerated. Experimental studies have shown that this missense change affects CTSA function (PMID: 8514852, 8968752, 10333491, 10944848). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, no assertion criteria provided	literature only	OMIM	Apr 14, 2015	- -
Pathogenic, criteria provided, single submitter	research	Lupski Lab, Baylor-Hopkins CMG, Baylor College of Medicine	Jul 01, 2014	- -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Aug 03, 2023	Variant summary: CTSA c.745T>A (p.Tyr249Asn) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 3.6e-05 in 251316 control chromosomes (gnomAD). c.745T>A has been reported in the literature in multiple individuals affected with Galactosialidosis (Zhou_1996, Shimmoto_1993, Lehman_2012, Prada_2014), and some were reported as compound heterozygous with other pathogenic variants. These data indicate that the variant is very likely to be associated with disease. Several publications report experimental evidence evaluating an impact on protein function, finding disruption in lysosomal compartmentalization, substantially reduced cathepsin A activity, and more modest reductions in beta-galactosidase and alpha-neuraminidase activity (Zhou_1996, Shimmoto_1993, Takiguchi_2000). The following publications have been ascertained in the context of this evaluation (PMID: 8968752, 8514852, 22386972, 10944848, 24769197). Two submitters have cited clinical-significance assessments for this variant to ClinVar after 2014, and classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -

Galactosialidosis, late infantile

Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Dec 01, 1996

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.26

BayesDel_addAF

Benign

-0.069

BayesDel_noAF

Benign

-0.14

Cadd

Uncertain

Dann

Benign

0.97

DEOGEN2

Uncertain

0.57

D;.;D;D;D;D

Eigen

Benign

-0.042

Eigen_PC

Benign

0.019

FATHMM_MKL

Uncertain

0.91

LIST_S2

Uncertain

0.94

D;D;.;.;D;D

M_CAP

Benign

0.071

MetaRNN

Uncertain

0.68

D;D;D;D;D;D

MetaSVM

Benign

-0.71

MutationTaster

Benign

1.0

A;A;A

PrimateAI

Benign

0.45

PROVEAN

Uncertain

-4.1

D;D;.;D;D;.

REVEL

Uncertain

0.46

Sift

Benign

0.050

D;T;.;D;T;.

Sift4G

Benign

0.074

T;T;.;T;T;D

Polyphen

0.23

.;.;B;B;B;.

Vest4

0.81

MutPred

0.80

.;.;Gain of disorder (P = 0.0339);Gain of disorder (P = 0.0339);Gain of disorder (P = 0.0339);.;

MVP

0.87

MPC

0.76

ClinPred

0.33

GERP RS

2.4

Varity_R

0.70

gMVP

0.83

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.070

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over