NM_003793.4:c.1375G>A

Variant names:

• chr11-66564093-C-T
• NM_003793.4:c.1375G>A

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_003793.4(CTSF):​c.1375G>A​(p.Glu459Lys) variant causes a missense change. The variant allele was found at a frequency of 0.00000205 in 1,461,346 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: CTSF NM_003793.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.04
• Publications: 0 publications found

Genes affected

CTSF (HGNC:2531): (cathepsin F) Cathepsins are papain family cysteine proteinases that represent a major component of the lysosomal proteolytic system. Cathepsins generally contain a signal sequence, followed by a propeptide and then a catalytically active mature region. The very long (251 amino acid residues) proregion of the cathepsin F precursor contains a C-terminal domain similar to the pro-segment of cathepsin L-like enzymes, a 50-residue flexible linker peptide, and an N-terminal domain predicted to adopt a cystatin-like fold. The cathepsin F proregion is unique within the papain family cysteine proteases in that it contains this additional N-terminal segment predicted to share structural similarities with cysteine protease inhibitors of the cystatin superfamily. This cystatin-like domain contains some of the elements known to be important for inhibitory activity. CTSF encodes a predicted protein of 484 amino acids which contains a 19 residue signal peptide. Cathepsin F contains five potential N-glycosylation sites, and it may be targeted to the endosomal/lysosomal compartment via the mannose 6-phosphate receptor pathway. The cathepsin F gene is ubiquitously expressed, and it maps to chromosome 11q13, close to the gene encoding cathepsin W. [provided by RefSeq, Jul 2008]

CTSF Gene-Disease associations (from GenCC):

• adult neuronal ceroid lipofuscinosis

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• neuronal ceroid lipofuscinosis 13

  Inheritance: AR, Unknown Classification: DEFINITIVE, STRONG, SUPPORTIVE, LIMITED Submitted by: Orphanet, Genomics England PanelApp, Labcorp Genetics (formerly Invitae), Ambry Genetics

ACMG classification

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.952

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_003793.4. 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
	CTSF	NM_003793.4	MANE Select	c.1375G>A	p.Glu459Lys	missense	Exon 12 of 13	NP_003784.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CTSF	ENST00000310325.10	TSL:1 MANE Select	c.1375G>A	p.Glu459Lys	missense	Exon 12 of 13	ENSP00000310832.5	Q9UBX1
	CTSF	ENST00000677587.1		c.1417G>A	p.Glu473Lys	missense	Exon 12 of 13	ENSP00000503791.1	A0A7I2V411
	CTSF	ENST00000524994.6	TSL:5	c.1372G>A	p.Glu458Lys	missense	Exon 12 of 13	ENSP00000433082.2	H0YD65

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1461346 Hom.: 0 Cov.: 33 AF XY: 0.00000413 AC XY: 3 AN XY: 726912

African (AFR) AF: 0.00 AC: 0 AN: 33476

American (AMR) AF: 0.00 AC: 0 AN: 44640

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26122

East Asian (EAS) AF: 0.00 AC: 0 AN: 39686

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86150

European-Finnish (FIN) AF: 0.0000188 AC: 1 AN: 53308

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1111834

Other (OTH) AF: 0.00 AC: 0 AN: 60362

GnomAD4 genome Cov.: 33

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.30
BayesDel_addAF	Pathogenic	0.24	D
BayesDel_noAF	Uncertain	0.10
CADD	Pathogenic	29
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.84	D
Eigen	Pathogenic	0.75
Eigen_PC	Uncertain	0.62
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	0.99	D
M_CAP	Benign	0.052	D
MetaRNN	Pathogenic	0.95	D
MetaSVM	Benign	-0.33	T
MutationAssessor	Pathogenic	3.6	H
PhyloP100		4.0
PrimateAI	Benign	0.45	T
PROVEAN	Uncertain	-3.5	D
REVEL	Uncertain	0.43
Sift	Uncertain	0.0030	D
Sift4G	Uncertain	0.0060	D
Polyphen		1.0	D
Vest4		0.59
MutPred		0.77		Gain of MoRF binding (P = 0.002)
MVP		0.69
MPC		0.78
ClinPred		0.99	D
GERP RS		4.8
Varity_R		0.88
gMVP		0.95
Mutation Taster		=37/63	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.42		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.42		Position offset: 3

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

Other links and lift over

hg19: chr11-66331564;