20-45891598-CCTGCTGCTGCTGCTGCTGCTGCTGCT-CCTGCTGCTGCTGCT

Variant names:

• chr20-45891598-CCTGCTGCTGCTG-C
• rs72555383
• NM_000308.4:c.45_56delGCTGCTGCTGCT

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 0P and 1B. BP3

The NM_000308.4(CTSA):​c.45_56delGCTGCTGCTGCT​(p.Leu16_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 0.0000278 in 1,581,938 control chromosomes in the GnomAD database, with no homozygous occurrence. It is difficult to determine the true allele frequency of this variant because it is of type DEL_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000087 (0 hom., cov: 0)
  • Exomes 𝑓: 0.000022 (0 hom.)
• Consequence: CTSA NM_000308.4 disruptive_inframe_deletion
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.48
• Publications: 1 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: ClinGen, Labcorp Genetics (formerly Invitae), Orphanet, Genomics England PanelApp, Illumina, G2P

ACMG classification

Our verdict: Likely_benign. The variant received -1 ACMG points.

• BP3: Nonframeshift variant in repetitive region in NM_000308.4

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000308.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CTSA	NM_000308.4	MANE Select	c.45_56delGCTGCTGCTGCT	p.Leu16_Leu19del	disruptive_inframe_deletion	Exon 2 of 15	NP_000299.3	P10619-1
	CTSA	NM_001127695.3		c.45_56delGCTGCTGCTGCT	p.Leu16_Leu19del	disruptive_inframe_deletion	Exon 2 of 15	NP_001121167.1	P10619-1
	CTSA	NM_001167594.3		c.45_56delGCTGCTGCTGCT	p.Leu16_Leu19del	disruptive_inframe_deletion	Exon 2 of 14	NP_001161066.2	P10619-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CTSA	ENST00000646241.3	MANE Select	c.45_56delGCTGCTGCTGCT	p.Leu16_Leu19del	disruptive_inframe_deletion	Exon 2 of 15	ENSP00000493613.2	P10619-1
	CTSA	ENST00000372484.8	TSL:1	c.99_110delGCTGCTGCTGCT	p.Leu34_Leu37del	disruptive_inframe_deletion	Exon 2 of 15	ENSP00000361562.3	X6R8A1
	CTSA	ENST00000191018.9	TSL:1	c.45_56delGCTGCTGCTGCT	p.Leu16_Leu19del	disruptive_inframe_deletion	Exon 2 of 15	ENSP00000191018.5	P10619-1

Frequencies

GnomAD3 genomes AF: 0.0000868 AC: 13 AN: 149794 Hom.: 0 Cov.: 0

Gnomad AFR AF: 0.000270

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000667

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.000485

GnomAD2 exomes AF: 0.0000442 AC: 9 AN: 203638 AF XY: 0.0000443

Gnomad AFR exome AF: 0.000751

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000216 AC: 31 AN: 1432030 Hom.: 0 AF XY: 0.0000224 AC XY: 16 AN XY: 712838

African (AFR) AF: 0.000517 AC: 17 AN: 32872

American (AMR) AF: 0.0000229 AC: 1 AN: 43594

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25792

East Asian (EAS) AF: 0.00 AC: 0 AN: 39148

South Asian (SAS) AF: 0.0000118 AC: 1 AN: 84808

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 46972

Middle Eastern (MID) AF: 0.000176 AC: 1 AN: 5688

European-Non Finnish (NFE) AF: 0.00000823 AC: 9 AN: 1093902

Other (OTH) AF: 0.0000338 AC: 2 AN: 59254

GnomAD4 genome AF: 0.0000867 AC: 13 AN: 149908 Hom.: 0 Cov.: 0 AF XY: 0.0000958 AC XY: 7 AN XY: 73070

African (AFR) AF: 0.000269 AC: 11 AN: 40844

American (AMR) AF: 0.0000666 AC: 1 AN: 15004

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3460

East Asian (EAS) AF: 0.00 AC: 0 AN: 4642

South Asian (SAS) AF: 0.00 AC: 0 AN: 4696

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10266

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67716

Other (OTH) AF: 0.000480 AC: 1 AN: 2082

Alfa AF: 0.00 Hom.: 2124

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Combined deficiency of sialidase AND beta galactosidase (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		2.5
Mutation Taster		=120/80	polymorphism

Splicing

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

Other links and lift over

dbSNP: rs72555383; hg19: chr20-44520237;