NM_000308.4:c.707T>C

Variant names:

• chr20-45894002-T-C
• rs137854546
• NM_000308.4:c.707T>C

Variant summary

Our verdict is Likely pathogenic. The variant received 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). Synonymous variant affecting the same amino acid position (i.e. L236L) has been classified as Likely benign.

• 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
• Publications: 6 publications found

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

ACMG classification

Our verdict: Likely_pathogenic. The variant received 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 VariationId is 384.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.707T>C	p.Leu236Pro	missense_variant	Exon 8 of 15	ENST00000646241.3	NP_000299.3
CTSA	NM_001127695.3	c.707T>C	p.Leu236Pro	missense_variant	Exon 8 of 15		NP_001121167.1
CTSA	NM_001167594.3	c.656T>C	p.Leu219Pro	missense_variant	Exon 7 of 14		NP_001161066.2
CTSA	NR_133656.2	n.759T>C		non_coding_transcript_exon_variant	Exon 8 of 15

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CTSA	ENST00000646241.3	c.707T>C	p.Leu236Pro	missense_variant	Exon 8 of 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

Dec 01, 1991

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

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;.
PhyloP100		7.2
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
Mutation Taster		=3/97	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
Splicevardb		2.0
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

Other links and lift over

dbSNP: rs137854546; hg19: chr20-44522641;