rs137854541

Positions:

• chr20-45891714-A-G

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM2 PP3 PP5_Very_Strong

The NM_000308.4(CTSA):​c.146A>G​(p.Gln49Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000372 in 1,613,392 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000027 (0 hom.)
• Consequence: CTSA NM_000308.4 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 8.86

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 Pathogenic. Variant got 11 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
• PP5: Variant 20-45891714-A-G is Pathogenic according to our data. Variant chr20-45891714-A-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 377.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CTSA	NM_000308.4	c.146A>G	p.Gln49Arg	missense_variant	2/15	ENST00000646241.3	NP_000299.3
CTSA	NM_001127695.3	c.146A>G	p.Gln49Arg	missense_variant	2/15		NP_001121167.1
CTSA	NM_001167594.3	c.146A>G	p.Gln49Arg	missense_variant	2/14		NP_001161066.2
CTSA	NR_133656.2	n.191A>G		non_coding_transcript_exon_variant	2/15

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CTSA	ENST00000646241.3	c.146A>G	p.Gln49Arg	missense_variant	2/15		NM_000308.4	ENSP00000493613

Frequencies

GnomAD3 genomes AF: 0.0000131 AC: 2 AN: 152184 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000274 AC: 4 AN: 1461208 Hom.: 0 Cov.: 35 AF XY: 0.00 AC XY: 0 AN XY: 726912

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000447

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: 0.00

Gnomad4 OTH exome AF: 0.0000331

GnomAD4 genome AF: 0.0000131 AC: 2 AN: 152184 Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2 AN XY: 74348

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.0000654

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Bravo AF: 0.0000189

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Combined deficiency of sialidase AND beta galactosidase Pathogenic:3

Likely pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 11, 2024	This sequence change replaces glutamine, which is neutral and polar, with arginine, which is basic and polar, at codon 67 of the CTSA protein (p.Gln67Arg). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with galactosialidosis (PMID: 8514852, 18396002, 26259553). This variant is also known as Q49R. ClinVar contains an entry for this variant (Variation ID: 377). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt CTSA protein function with a positive predictive value of 80%. Experimental studies have shown that this missense change affects CTSA function (PMID: 8514852). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jul 25, 2023	Variant summary: CTSA c.146A>G (p.Gln49Arg) results in a conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 249136 control chromosomes (gnomAD). c.146A>G has been reported in the literature in individuals affected with Galactosialidosis (Shimmoto_1993, Hossain_2016, Matsumoto_2008). These data indicate that the variant is likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function, finding that cells with the variant protein lacked carboxypeptidase, alpha-neuraminidase, and beta-galactosidase activity (Shimmoto_1993). The following publications have been ascertained in the context of this evaluation (PMID: 8514852, 26259553, 18396002). No submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as pathogenic. -
Pathogenic, no assertion criteria provided	literature only	OMIM	Jun 01, 1993	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.86
BayesDel_addAF	Pathogenic	0.41	D
BayesDel_noAF	Pathogenic	0.34
CADD	Pathogenic	34
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.62	D;.;D;D;D;D
Eigen	Pathogenic	0.90
Eigen_PC	Pathogenic	0.81
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	1.0	D;D;.;.;D;D
M_CAP	Uncertain	0.28	D
MetaRNN	Pathogenic	0.98	D;D;D;D;D;D
MetaSVM	Pathogenic	0.90	D
MutationAssessor	Pathogenic	3.8	.;.;H;H;.;H
MutationTaster	Benign	1.0	A;A;A
PrimateAI	Benign	0.46	T
PROVEAN	Uncertain	-2.5	N;N;.;N;.;D
REVEL	Pathogenic	0.87
Sift	Uncertain	0.011	D;D;.;D;.;D
Sift4G	Benign	0.074	T;T;.;T;T;T
Polyphen		1.0	.;.;D;D;.;D
Vest4		0.81
MutPred		0.94		.;.;Gain of MoRF binding (P = 0.0236);Gain of MoRF binding (P = 0.0236);Gain of MoRF binding (P = 0.0236);Gain of MoRF binding (P = 0.0236);
MVP		0.97
MPC		1.2
ClinPred		1.0	D
GERP RS		5.4
Varity_R		0.91
gMVP		0.87

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.65		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.65		Position offset: 0

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs137854541; hg19: chr20-44520353;