20-45898068-T-G

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 14 ACMG points: 14P and 0B. PM2PP3_StrongPP5_Very_Strong

The NM_000308.4(CTSA):c.1318T>G(p.Phe440Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000496 in 1,613,876 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 Likely pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. F440F) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000034 ( 0 hom. )

Consequence

CTSA
NM_000308.4 missense

Scores

Clinical Significance

Likely pathogenic criteria provided, multiple submitters, no conflicts P:4

Conservation

PhyloP100: 7.69

Publications

6 publications found

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 Gene-Disease associations (from GenCC):

galactosialidosis
Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: G2P, Labcorp Genetics (formerly Invitae), Genomics England PanelApp, Orphanet, ClinGen, Illumina

CTSA links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 14 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.981

PP5

Variant 20-45898068-T-G is Pathogenic according to our data. Variant chr20-45898068-T-G is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 375.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000308.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
CTSA	NM_000308.4	MANE Select	c.1318T>G	p.Phe440Val	missense	Exon 14 of 15	NP_000299.3
CTSA	NM_001127695.3		c.1318T>G	p.Phe440Val	missense	Exon 14 of 15	NP_001121167.1
CTSA	NM_001167594.3		c.1267T>G	p.Phe423Val	missense	Exon 13 of 14	NP_001161066.2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
CTSA	ENST00000646241.3	MANE Select	c.1318T>G	p.Phe440Val	missense	Exon 14 of 15	ENSP00000493613.2
CTSA	ENST00000372484.8	TSL:1	c.1372T>G	p.Phe458Val	missense	Exon 14 of 15	ENSP00000361562.3
CTSA	ENST00000191018.9	TSL:1	c.1318T>G	p.Phe440Val	missense	Exon 14 of 15	ENSP00000191018.5

Frequencies

GnomAD3 genomes

AF:

0.0000197

AC:

AN:

151994

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000483

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:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.00000795

AC:

AN:

251430

AF XY:

0.0000147

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 FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000176

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000342

AC:

AN:

1461882

Hom.:

Cov.:

AF XY:

0.00000550

AC XY:

AN XY:

727246

show subpopulations

African (AFR)

AF:

0.0000299

AC:

AN:

33480

American (AMR)

AF:

0.00

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.00

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53414

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00000360

AC:

AN:

1112006

Other (OTH)

AF:

0.00

AC:

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.485

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.0000197

AC:

AN:

151994

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74216

show subpopulations

African (AFR)

AF:

0.0000483

AC:

AN:

41386

American (AMR)

AF:

0.00

AC:

AN:

15272

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5146

South Asian (SAS)

AF:

0.00

AC:

AN:

4818

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10608

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000147

AC:

AN:

67972

Other (OTH)

AF:

0.00

AC:

AN:

2092

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.575

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00000859

Hom.:

ExAC

AF:

0.00000824

AC:

EpiCase

AF:

0.00

EpiControl

AF:

0.0000593

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Combined deficiency of sialidase AND beta galactosidase

Pathogenic:2

Apr 01, 2024

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant summary: CTSA c.1318T>G (p.Phe440Val) 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 8e-06 in 251430 control chromosomes (gnomAD). c.1318T>G has been reported in the literature in individuals affected with Galactosialidosis (examples: Zhou_1991, Zhou_1996). These data indicate that the variant may be associated with disease. At least one publication reports experimental evidence that this missense change affects CTSA function (Zhou_1991). The following publications have been ascertained in the context of this evaluation (PMID: 1756715, 8968752, 9435242). ClinVar contains an entry for this variant (Variation ID: 375). Based on the evidence outlined above, the variant was classified as likely pathogenic.

Dec 05, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces phenylalanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 458 of the CTSA protein (p.Phe458Val). This variant is present in population databases (rs137854540, gnomAD 0.004%). This missense change has been observed in individuals with galactosialidosis (PMID: 1756715, 8968752). This variant is also known as p.Phe412Val. ClinVar contains an entry for this variant (Variation ID: 375). 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 disruptive. Experimental studies have shown that this missense change affects CTSA function (PMID: 1756715). 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.

GALACTOSIALIDOSIS, LATE INFANTILE

Pathogenic:1

Dec 01, 1996

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

not provided

Pathogenic:1

Feb 09, 2024

GeneDx

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Published functional studies demonstrate a damaging effect (PMID: 1756715); Not observed at significant frequency in large population cohorts (gnomAD); Also known as p.(F412V); This variant is associated with the following publications: (PMID: 2148053, 9435242, 26659599, 20507906, 11212324, 1756715, 26147798, 28603679, 8968752, 23915561, 3149149)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.92

BayesDel_addAF

Pathogenic

0.41

BayesDel_noAF

Pathogenic

0.37

CADD

Uncertain

(source)

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.61

Eigen

Pathogenic

0.73

Eigen_PC

Pathogenic

0.69

FATHMM_MKL

Uncertain

0.96

LIST_S2

Uncertain

0.91

M_CAP

Pathogenic

0.37

MetaRNN

Pathogenic

0.98

MetaSVM

Uncertain

0.62

MutationAssessor

Uncertain

2.3

PhyloP100

7.7

PrimateAI

Uncertain

0.74

PROVEAN

Pathogenic

-5.9

REVEL

Pathogenic

0.93

Sift

Uncertain

0.0020

Sift4G

Uncertain

0.0030

Polyphen

1.0

Vest4

0.89

MutPred

0.87

Gain of sheet (P = 0.0827)

MVP

0.99

MPC

1.0

ClinPred

0.99

GERP RS

5.5

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.95

gMVP

0.78

Mutation Taster

=1/99

disease causing (ClinVar)

(source)

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over