20-45891598-CCTGCTGCTGCTGCTGCTGCTGCTGCT-CCTGCTGCTGCTGCTGCTGCTGCT

Position:

• chr20-45891598-CCTGCTGCTGCTGCTGCTGCTGCTGCT-CCTGCTGCTGCTGCTGCTGCTGCT

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP6_Very_Strong BA1

The NM_000308.4(CTSA):​c.54_56delGCT​(p.Leu19del) variant causes a disruptive inframe deletion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.612 in 1,575,580 control chromosomes in the GnomAD database, including 278,356 homozygotes. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.66 (31868 hom., cov: 0)
  • Exomes 𝑓: 0.61 (246488 hom.)
• Consequence: CTSA NM_000308.4 disruptive_inframe_deletion
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:13
• Conservation: PhyloP100: 2.48

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 Benign. Variant got -16 ACMG points.

• BP6: Variant 20-45891598-CCTG-C is Benign according to our data. Variant chr20-45891598-CCTG-C is described in ClinVar as [Benign]. Clinvar id is 195059.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr20-45891598-CCTG-C is described in Lovd as [Benign]. Variant chr20-45891598-CCTG-C is described in Lovd as [Likely_benign]. Variant chr20-45891598-CCTG-C is described in Lovd as [Likely_benign].
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.695 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CTSA	NM_000308.4	c.54_56delGCT	p.Leu19del	disruptive_inframe_deletion	2/15	ENST00000646241.3	NP_000299.3
CTSA	NM_001127695.3	c.54_56delGCT	p.Leu19del	disruptive_inframe_deletion	2/15		NP_001121167.1
CTSA	NM_001167594.3	c.54_56delGCT	p.Leu19del	disruptive_inframe_deletion	2/14		NP_001161066.2
CTSA	NR_133656.2	n.99_101delGCT		non_coding_transcript_exon_variant	2/15

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CTSA	ENST00000646241.3	c.54_56delGCT	p.Leu19del	disruptive_inframe_deletion	2/15		NM_000308.4	ENSP00000493613.2

Frequencies

GnomAD3 genomes AF: 0.655 AC: 98069 AN: 149708 Hom.: 31815 Cov.: 0

Gnomad AFR AF: 0.687

Gnomad AMI AF: 0.590

Gnomad AMR AF: 0.706

Gnomad ASJ AF: 0.532

Gnomad EAS AF: 0.616

Gnomad SAS AF: 0.657

Gnomad FIN AF: 0.681

Gnomad MID AF: 0.595

Gnomad NFE AF: 0.631

Gnomad OTH AF: 0.642

GnomAD3 exomes AF: 0.623 AC: 126967 AN: 203638 Hom.: 37576 AF XY: 0.620 AC XY: 69969 AN XY: 112766

Gnomad AFR exome AF: 0.659

Gnomad AMR exome AF: 0.697

Gnomad ASJ exome AF: 0.485

Gnomad EAS exome AF: 0.590

Gnomad SAS exome AF: 0.623

Gnomad FIN exome AF: 0.664

Gnomad NFE exome AF: 0.608

Gnomad OTH exome AF: 0.603

GnomAD4 exome AF: 0.607 AC: 865716 AN: 1425758 Hom.: 246488 AF XY: 0.606 AC XY: 430222 AN XY: 709556

Gnomad4 AFR exome AF: 0.648

Gnomad4 AMR exome AF: 0.666

Gnomad4 ASJ exome AF: 0.499

Gnomad4 EAS exome AF: 0.563

Gnomad4 SAS exome AF: 0.609

Gnomad4 FIN exome AF: 0.637

Gnomad4 NFE exome AF: 0.607

Gnomad4 OTH exome AF: 0.597

GnomAD4 genome AF: 0.655 AC: 98180 AN: 149822 Hom.: 31868 Cov.: 0 AF XY: 0.657 AC XY: 47994 AN XY: 73024

Gnomad4 AFR AF: 0.687

Gnomad4 AMR AF: 0.706

Gnomad4 ASJ AF: 0.532

Gnomad4 EAS AF: 0.616

Gnomad4 SAS AF: 0.657

Gnomad4 FIN AF: 0.681

Gnomad4 NFE AF: 0.631

Gnomad4 OTH AF: 0.645

Bravo AF: 0.668

ClinVar

Significance: Benign

Submissions summary: Benign:13

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:5

Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	May 19, 2015	- -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Apr 06, 2023	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 28, 2016	Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: 64% of total chromosomes in ExAC -

not provided Benign:4

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 13, 2018	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Benign, no assertion criteria provided	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Mar 15, 2017	- -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Benign, flagged submission	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Nov 22, 2017	Variant summary: The CTSA c.108_110delGCT (p.Leu37del) variant involves the deletion of a luecine in a string of 9 leucines. One in silico tool predicts a polymorphism outcome for this variant. This variant was found in 144801/230752 control chromosomes (43432 homozygotes) at a frequency of 0.6275179, which is approximately 397 times the estimated maximal expected allele frequency of a pathogenic CTSA variant (0.0015811), suggesting this variant is likely a benign polymorphism. Taken together, this variant is classified as benign. One case report cites the variant in a GSL patient, along with two other variants that have not been reported by other clinical labs, therefore it is unclear which variants are disease-causing. Multiple clinical diagnostic laboratories/reputable databases classified this variant as benign. Taken together, this variant is classified as benign. -

Combined deficiency of sialidase AND beta galactosidase Benign:4

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 03, 2025	- -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 30, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Molecular Genetics, Royal Melbourne Hospital	May 04, 2023	Latino/Admixed American population allele frequency is 68.93%% (rs781707830, 126967/203638 alleles, 37576 homozygotes in gnomAD v2.1). Based on the classification scheme RMH Modified ACMG/AMP Guidelines v1.1.0, this variant is classified as BENIGN. Following criteria are met: BA1 -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jun 14, 2016	- -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs72555383; hg19: chr20-44520237;