NM_000308.4:c.48_56dupGCTGCTGCT

Variant names:

• chr20-45891598-C-CCTGCTGCTG
• rs72555383
• NM_000308.4:c.48_56dupGCTGCTGCT

Variant summary

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

The NM_000308.4(CTSA):​c.48_56dupGCTGCTGCT​(p.Leu17_Leu19dup) variant causes a disruptive inframe insertion change involving the alteration of a non-conserved nucleotide. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. L19L) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.000053 (0 hom., cov: 0)
  • Exomes 𝑓: 0.000025 (0 hom.)
• Consequence: CTSA NM_000308.4 disruptive_inframe_insertion
• 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.48_56dupGCTGCTGCT	p.Leu17_Leu19dup	disruptive_inframe_insertion	Exon 2 of 15	NP_000299.3	P10619-1
	CTSA	NM_001127695.3		c.48_56dupGCTGCTGCT	p.Leu17_Leu19dup	disruptive_inframe_insertion	Exon 2 of 15	NP_001121167.1	P10619-1
	CTSA	NM_001167594.3		c.48_56dupGCTGCTGCT	p.Leu17_Leu19dup	disruptive_inframe_insertion	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.48_56dupGCTGCTGCT	p.Leu17_Leu19dup	disruptive_inframe_insertion	Exon 2 of 15	ENSP00000493613.2	P10619-1
	CTSA	ENST00000372484.8	TSL:1	c.102_110dupGCTGCTGCT	p.Leu35_Leu37dup	disruptive_inframe_insertion	Exon 2 of 15	ENSP00000361562.3	X6R8A1
	CTSA	ENST00000191018.9	TSL:1	c.48_56dupGCTGCTGCT	p.Leu17_Leu19dup	disruptive_inframe_insertion	Exon 2 of 15	ENSP00000191018.5	P10619-1

Frequencies

GnomAD3 genomes AF: 0.0000534 AC: 8 AN: 149796 Hom.: 0 Cov.: 0

Gnomad AFR AF: 0.0000737

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000667

Gnomad ASJ AF: 0.000578

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000213

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000148

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000491 AC: 10 AN: 203638 AF XY: 0.0000798

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.000568

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000606

Gnomad NFE exome AF: 0.0000219

Gnomad OTH exome AF: 0.000196

GnomAD4 exome AF: 0.0000251 AC: 36 AN: 1432032 Hom.: 0 Cov.: 0 AF XY: 0.0000295 AC XY: 21 AN XY: 712840

African (AFR) AF: 0.0000304 AC: 1 AN: 32872

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

Ashkenazi Jewish (ASJ) AF: 0.000504 AC: 13 AN: 25792

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

South Asian (SAS) AF: 0.0000236 AC: 2 AN: 84808

European-Finnish (FIN) AF: 0.0000639 AC: 3 AN: 46974

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5688

European-Non Finnish (NFE) AF: 0.0000110 AC: 12 AN: 1093902

Other (OTH) AF: 0.0000675 AC: 4 AN: 59254

GnomAD4 genome AF: 0.0000534 AC: 8 AN: 149796 Hom.: 0 Cov.: 0 AF XY: 0.0000548 AC XY: 4 AN XY: 72950

African (AFR) AF: 0.0000737 AC: 3 AN: 40726

American (AMR) AF: 0.0000667 AC: 1 AN: 14984

Ashkenazi Jewish (ASJ) AF: 0.000578 AC: 2 AN: 3460

East Asian (EAS) AF: 0.00 AC: 0 AN: 4652

South Asian (SAS) AF: 0.000213 AC: 1 AN: 4702

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

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000148 AC: 1 AN: 67726

Other (OTH) AF: 0.00 AC: 0 AN: 2060

Alfa AF: 0.000198 Hom.: 2124

Bravo AF: 0.0000491

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		=78/22	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;