Genetic Variant CTSA:p.Ala337Thr (chr20-45895054-G-A) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_000308.4(CTSA):c.1009G>A(p.Ala337Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,461,882 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 17/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A337P) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000021 ( 0 hom. )

Consequence

CTSA
NM_000308.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.890

Publications

1 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: ClinGen, Labcorp Genetics (formerly Invitae), Orphanet, Genomics England PanelApp, Illumina, G2P

CTSA links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.0887337).

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	UniProt
CTSA	NM_000308.4	MANE Select	c.1009G>A	p.Ala337Thr	missense	Exon 11 of 15	NP_000299.3	P10619-1
CTSA	NM_001127695.3		c.1009G>A	p.Ala337Thr	missense	Exon 11 of 15	NP_001121167.1	P10619-1
CTSA	NM_001167594.3		c.958G>A	p.Ala320Thr	missense	Exon 10 of 14	NP_001161066.2	P10619-2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
CTSA	ENST00000646241.3	MANE Select	c.1009G>A	p.Ala337Thr	missense	Exon 11 of 15	ENSP00000493613.2	P10619-1
CTSA	ENST00000372484.8	TSL:1	c.1063G>A	p.Ala355Thr	missense	Exon 11 of 15	ENSP00000361562.3	X6R8A1
CTSA	ENST00000191018.9	TSL:1	c.1009G>A	p.Ala337Thr	missense	Exon 11 of 15	ENSP00000191018.5	P10619-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000205

AC:

AN:

1461882

Hom.:

Cov.:

AF XY:

0.00000413

AC XY:

AN XY:

727242

show subpopulations

African (AFR)

AF:

0.00

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:

39698

South Asian (SAS)

AF:

0.00

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.0000187

AC:

AN:

53416

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

8.99e-7

AC:

AN:

1112006

Other (OTH)

AF:

0.0000166

AC:

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.090

BayesDel_addAF

Benign

-0.088

BayesDel_noAF

Benign

-0.36

CADD

Benign

2.0

(source)

DANN

Benign

0.84

DEOGEN2

Benign

0.21

Eigen

Benign

-1.6

Eigen_PC

Benign

-1.7

FATHMM_MKL

Benign

0.088

LIST_S2

Benign

0.74

M_CAP

Benign

0.023

MetaRNN

Benign

0.089

MetaSVM

Benign

-0.85

MutationAssessor

Benign

0.050

PhyloP100

-0.89

PrimateAI

Benign

0.23

PROVEAN

Benign

0.020

REVEL

Benign

0.23

Sift

Benign

0.56

Sift4G

Benign

0.58

Polyphen

0.0

Vest4

0.11

MutPred

0.67

Gain of glycosylation at A337 (P = 0.0251)

MVP

0.68

MPC

0.37

ClinPred

0.039

GERP RS

-11

Varity_R

0.21

gMVP

0.36

Mutation Taster

=90/10

polymorphism

(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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over