NM_000308.4:c.54_56delGCT

Variant names:

• chr20-45891598-CCTG-C
• rs72555383
• NM_000308.4:c.54_56delGCT

Variant summary

Our verdict is Benign. The variant received -17 ACMG points: 0P and 17B. BP3 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 (★★). Synonymous variant affecting the same amino acid position (i.e. L18L) has been classified as Likely 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
• 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: Benign. The variant received -17 ACMG points.

• BP3: Nonframeshift variant in repetitive region in NM_000308.4
• BP6: Variant 20-45891598-CCTG-C is Benign according to our data. Variant chr20-45891598-CCTG-C is described in ClinVar as Benign. ClinVar VariationId is 195059.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.695 is higher than 0.05.

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.54_56delGCT	p.Leu19del	disruptive_inframe_deletion	Exon 2 of 15	NP_000299.3	P10619-1
	CTSA	NM_001127695.3		c.54_56delGCT	p.Leu19del	disruptive_inframe_deletion	Exon 2 of 15	NP_001121167.1	P10619-1
	CTSA	NM_001167594.3		c.54_56delGCT	p.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.54_56delGCT	p.Leu19del	disruptive_inframe_deletion	Exon 2 of 15	ENSP00000493613.2	P10619-1
	CTSA	ENST00000372484.8	TSL:1	c.108_110delGCT	p.Leu37del	disruptive_inframe_deletion	Exon 2 of 15	ENSP00000361562.3	X6R8A1
	CTSA	ENST00000191018.9	TSL:1	c.54_56delGCT	p.Leu19del	disruptive_inframe_deletion	Exon 2 of 15	ENSP00000191018.5	P10619-1

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

GnomAD2 exomes AF: 0.623 AC: 126967 AN: 203638 AF XY: 0.620

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 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

African (AFR) AF: 0.648 AC: 21221 AN: 32756

American (AMR) AF: 0.666 AC: 28937 AN: 43444

Ashkenazi Jewish (ASJ) AF: 0.499 AC: 12742 AN: 25552

East Asian (EAS) AF: 0.563 AC: 21940 AN: 38992

South Asian (SAS) AF: 0.609 AC: 51372 AN: 84374

European-Finnish (FIN) AF: 0.637 AC: 29772 AN: 46752

Middle Eastern (MID) AF: 0.557 AC: 3155 AN: 5662

European-Non Finnish (NFE) AF: 0.607 AC: 661390 AN: 1089286

Other (OTH) AF: 0.597 AC: 35187 AN: 58940

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

African (AFR) AF: 0.687 AC: 28031 AN: 40818

American (AMR) AF: 0.706 AC: 10588 AN: 14990

Ashkenazi Jewish (ASJ) AF: 0.532 AC: 1838 AN: 3458

East Asian (EAS) AF: 0.616 AC: 2857 AN: 4638

South Asian (SAS) AF: 0.657 AC: 3086 AN: 4696

European-Finnish (FIN) AF: 0.681 AC: 6984 AN: 10254

Middle Eastern (MID) AF: 0.605 AC: 178 AN: 294

European-Non Finnish (NFE) AF: 0.631 AC: 42743 AN: 67690

Other (OTH) AF: 0.645 AC: 1342 AN: 2080

Alfa AF: 0.517 Hom.: 2124

Bravo AF: 0.668

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	not specified (5)
-	-	4	Combined deficiency of sialidase AND beta galactosidase (4)
-	-	4	not provided (4)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		2.5
Mutation Taster		=86/14	polymorphism (auto)

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs72555383; hg19: chr20-44520237; COSMIC: COSV51940368; COSMIC: COSV51940368;