rs137854546

Positions:

• chr20-45894002-T-C

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.707T>C​(p.Leu236Pro) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars).

• Frequency: Genomes: not found (cov: 33)
• Consequence: CTSA NM_000308.4 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 7.20

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 (HGNC:):

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, 0.983
• PP5: Variant 20-45894002-T-C is Pathogenic according to our data. Variant chr20-45894002-T-C is described in ClinVar as [Pathogenic]. Clinvar id is 384.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CTSA	NM_000308.4	c.707T>C	p.Leu236Pro	missense_variant	8/15	ENST00000646241.3	NP_000299.3
CTSA	NM_001127695.3	c.707T>C	p.Leu236Pro	missense_variant	8/15		NP_001121167.1
CTSA	NM_001167594.3	c.656T>C	p.Leu219Pro	missense_variant	7/14		NP_001161066.2
CTSA	NR_133656.2	n.759T>C		non_coding_transcript_exon_variant	8/15

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CTSA	ENST00000646241.3	c.707T>C	p.Leu236Pro	missense_variant	8/15		NM_000308.4	ENSP00000493613.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Galactosialidosis, early infantile Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Dec 01, 1991

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.39	D
BayesDel_noAF	Pathogenic	0.33
CADD	Pathogenic	30
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.76	D;.;D;D;D;D
Eigen	Pathogenic	0.76
Eigen_PC	Pathogenic	0.67
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.91	D;D;.;.;D;D
M_CAP	Pathogenic	0.30	D
MetaRNN	Pathogenic	0.98	D;D;D;D;D;D
MetaSVM	Uncertain	0.28	D
MutationAssessor	Pathogenic	4.0	.;.;H;H;H;.
PrimateAI	Uncertain	0.70	T
PROVEAN	Pathogenic	-7.0	D;D;.;D;D;.
REVEL	Pathogenic	0.83
Sift	Pathogenic	0.0	D;D;.;D;D;.
Sift4G	Uncertain	0.0020	D;D;.;D;D;D
Polyphen		1.0	.;.;D;D;D;.
Vest4		0.93
MutPred		0.92		.;.;Loss of stability (P = 0.0112);Loss of stability (P = 0.0112);Loss of stability (P = 0.0112);.;
MVP		0.96
MPC		1.5
ClinPred		1.0	D
GERP RS		4.4
Varity_R		0.98
gMVP		0.99

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs137854546; hg19: chr20-44522641;