rs137854549

Variant names:

• chr20-45898107-A-G
• rs137854549
• NM_000308.4:c.1357A>G

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM2 PP3_Strong PP5

The NM_000308.4(CTSA):​c.1357A>G​(p.Lys453Glu) variant causes a missense, splice region change. 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: 0.8475
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 6.93

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 7 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.977
• PP5: Variant 20-45898107-A-G is Pathogenic according to our data. Variant chr20-45898107-A-G is described in ClinVar as [Pathogenic]. Clinvar id is 388.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CTSA	NM_000308.4	c.1357A>G	p.Lys453Glu	missense_variant, splice_region_variant	Exon 14 of 15	ENST00000646241.3	NP_000299.3
CTSA	NM_001127695.3	c.1357A>G	p.Lys453Glu	missense_variant, splice_region_variant	Exon 14 of 15		NP_001121167.1
CTSA	NM_001167594.3	c.1306A>G	p.Lys436Glu	missense_variant, splice_region_variant	Exon 13 of 14		NP_001161066.2
CTSA	NR_133656.2	n.1409A>G		splice_region_variant, non_coding_transcript_exon_variant	Exon 14 of 15

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CTSA	ENST00000646241.3	c.1357A>G	p.Lys453Glu	missense_variant, splice_region_variant	Exon 14 of 15		NM_000308.4	ENSP00000493613.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Galactosialidosis, late infantile Pathogenic:1

Jan 01, 2000

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.95
BayesDel_addAF	Pathogenic	0.48	D
BayesDel_noAF	Pathogenic	0.45
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.61	D;.;D;D;D
Eigen	Pathogenic	0.83
Eigen_PC	Pathogenic	0.77
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.97	D;D;.;.;D
M_CAP	Pathogenic	0.52	D
MetaRNN	Pathogenic	0.98	D;D;D;D;D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Pathogenic	3.0	.;.;M;M;M
PrimateAI	Uncertain	0.73	T
PROVEAN	Uncertain	-3.3	D;D;.;D;.
REVEL	Pathogenic	0.93
Sift	Uncertain	0.0040	D;D;.;D;.
Sift4G	Uncertain	0.0060	D;D;.;D;D
Polyphen		1.0	.;.;D;D;D
Vest4		0.89
MutPred		0.89		.;.;Loss of methylation at K453 (P = 0.0179);Loss of methylation at K453 (P = 0.0179);Loss of methylation at K453 (P = 0.0179);
MVP		0.99
MPC		1.3
ClinPred		0.98	D
GERP RS		5.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.7
Varity_R		0.96
gMVP		0.87

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.85
dbscSNV1_RF	Pathogenic	0.79
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: rs137854549; hg19: chr20-44526746;