20-45891598-CCTGCTGCTGCTGCTGCTGCTGCTGCT-CCTGCTGCTGCTGCTGCTGCTGCTGCTGCT

Position:

• chr20-45891598-CCTGCTGCTGCTGCTGCTGCTGCTGCT-CCTGCTGCTGCTGCTGCTGCTGCTGCTGCT

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP6_Very_Strong BS1 BS2

The NM_000308.4(CTSA):​c.54_56dup​(p.Leu18dup) variant causes a inframe insertion change involving the alteration of a non-conserved nucleotide. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0046 (1 hom., cov: 0)
  • Exomes 𝑓: 0.0059 (7 hom.)
• Consequence: CTSA NM_000308.4 inframe_insertion
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• 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-C-CCTG is Benign according to our data. Variant chr20-45891598-C-CCTG is described in ClinVar as [Likely_benign]. Clinvar id is 632780.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00464 (696/149906) while in subpopulation NFE AF= 0.00777 (526/67714). AF 95% confidence interval is 0.00722. There are 1 homozygotes in gnomad4. There are 303 alleles in male gnomad4 subpopulation. Median coverage is 0. This position pass quality control queck.
• BS2: High Homozygotes in GnomAdExome4 at 7 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CTSA	NM_000308.4	c.54_56dup	p.Leu18dup	inframe_insertion	2/15	ENST00000646241.3
CTSA	NM_001127695.3	c.54_56dup	p.Leu18dup	inframe_insertion	2/15
CTSA	NM_001167594.3	c.54_56dup	p.Leu18dup	inframe_insertion	2/14
CTSA	NR_133656.2	n.99_101dup		non_coding_transcript_exon_variant	2/15

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CTSA	ENST00000646241.3	c.54_56dup	p.Leu18dup	inframe_insertion	2/15		NM_000308.4

Frequencies

GnomAD3 genomes AF: 0.00465 AC: 696 AN: 149792 Hom.: 1 Cov.: 0

Gnomad AFR AF: 0.000884

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00380

Gnomad ASJ AF: 0.0110

Gnomad EAS AF: 0.00107

Gnomad SAS AF: 0.00106

Gnomad FIN AF: 0.00214

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00777

Gnomad OTH AF: 0.00291

GnomAD3 exomes AF: 0.00573 AC: 1167 AN: 203638 Hom.: 5 AF XY: 0.00565 AC XY: 637 AN XY: 112766

Gnomad AFR exome AF: 0.00134

Gnomad AMR exome AF: 0.00328

Gnomad ASJ exome AF: 0.0124

Gnomad EAS exome AF: 0.000683

Gnomad SAS exome AF: 0.00151

Gnomad FIN exome AF: 0.00249

Gnomad NFE exome AF: 0.00908

Gnomad OTH exome AF: 0.00529

GnomAD4 exome AF: 0.00585 AC: 8382 AN: 1432024 Hom.: 7 Cov.: 0 AF XY: 0.00571 AC XY: 4068 AN XY: 712836

Gnomad4 AFR exome AF: 0.000882

Gnomad4 AMR exome AF: 0.00248

Gnomad4 ASJ exome AF: 0.0110

Gnomad4 EAS exome AF: 0.000715

Gnomad4 SAS exome AF: 0.00123

Gnomad4 FIN exome AF: 0.00226

Gnomad4 NFE exome AF: 0.00675

Gnomad4 OTH exome AF: 0.00545

GnomAD4 genome AF: 0.00464 AC: 696 AN: 149906 Hom.: 1 Cov.: 0 AF XY: 0.00415 AC XY: 303 AN XY: 73070

Gnomad4 AFR AF: 0.000881

Gnomad4 AMR AF: 0.00380

Gnomad4 ASJ AF: 0.0110

Gnomad4 EAS AF: 0.00108

Gnomad4 SAS AF: 0.00106

Gnomad4 FIN AF: 0.00214

Gnomad4 NFE AF: 0.00777

Gnomad4 OTH AF: 0.00288

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Jun 15, 2018

Variant summary: CTSA c.108_110dupGCT (p.Leu37dup) results in an in-frame insertion of a leucine into a repetitive region of the encoded protein sequence; this region consists of several consecutive leucines and doesn't have a known function. The variant allele was found at a frequency of 0.0055 in 230752 control chromosomes in the gnomAD database, including 5 homozygotes. The observed variant frequency is approximately 3.46 fold of the estimated maximal expected allele frequency for a pathogenic variant in CTSA causing Galactosialidosis phenotype (0.0016), strongly suggesting that the variant is benign. To our knowledge, no occurrence of c.108_110dupGCT in individuals affected with Galactosialidosis and no experimental evidence demonstrating its impact on protein function have been reported. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as benign. -

CTSA-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Apr 15, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Mar 01, 2024

CTSA: BS2 -

Combined deficiency of sialidase AND beta galactosidase Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 31, 2024

- -

Computational scores

Source: dbNSFP v4.3

Splicing

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;