20-45891337-T-A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The ENST00000372484.8(CTSA):c.12T>A(p.Ser4Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000893 in 1,567,414 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0000092 ( 0 hom. )

Consequence

CTSA
ENST00000372484.8 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -0.0560

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 Uncertain_significance. Variant got 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.06829366).

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	#exon/exons	MANE
CTSA	NM_000308.4 linkuse as main transcript	c.-43T>A	5_prime_UTR_variant	1/15	ENST00000646241.3
CTSA	NM_001127695.3 linkuse as main transcript	c.-89T>A	5_prime_UTR_variant	1/15
CTSA	NM_001167594.3 linkuse as main transcript	c.-43T>A	5_prime_UTR_variant	1/14
CTSA	NR_133656.2 linkuse as main transcript	n.3T>A	non_coding_transcript_exon_variant	1/15

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CTSA	ENST00000646241.3 linkuse as main transcript	c.-43T>A		5_prime_UTR_variant	1/15		NM_000308.4		P10619-1

Frequencies

GnomAD3 genomes

AF:

0.00000658

AC:

AN:

151986

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:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.00000918

AC:

AN:

1415428

Hom.:

Cov.:

AF XY:

0.00000572

AC XY:

AN XY:

699766

show subpopulations

Gnomad4 AFR exome

AF:

0.0000308

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:

0.00000919

Gnomad4 OTH exome

AF:

0.0000341

GnomAD4 genome

AF:

0.00000658

AC:

AN:

151986

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74248

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:

0.0000147

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.00000378

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000259

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Combined deficiency of sialidase AND beta galactosidase

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Oct 27, 2021

This sequence change replaces serine, which is neutral and polar, with arginine, which is basic and polar, at codon 4 of the CTSA protein (p.Ser4Arg). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with CTSA-related conditions. Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Not Available"; PolyPhen-2: "Benign"; Align-GVGD: "Not Available". The arginine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. 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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Benign

-0.23

BayesDel_noAF

Benign

-0.56

Cadd

Benign

Dann

Benign

0.82

DEOGEN2

Benign

0.0053

T;.

Eigen

Benign

-0.85

Eigen_PC

Benign

-0.93

FATHMM_MKL

Benign

0.75

LIST_S2

Benign

0.57

T;T

M_CAP

Benign

0.017

MetaRNN

Benign

0.068

T;T

MetaSVM

Benign

-1.0

MutationTaster

Benign

1.0

N;N

PrimateAI

Benign

0.47

PROVEAN

Benign

-0.21

N;N

REVEL

Benign

0.011

Sift

Benign

0.56

T;T

Sift4G

Benign

0.56

T;T

Vest4

0.077

MutPred

0.14

Loss of phosphorylation at S4 (P = 0.0059);Loss of phosphorylation at S4 (P = 0.0059);

MVP

0.21

MPC

0.43

ClinPred

0.15

GERP RS

0.11

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

gMVP

0.52

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.11

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