11-66568361-G-C

Variant names:

• chr11-66568361-G-C
• rs1044522
• NM_003793.4:c.126C>G

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 2P and 5B. PM2 BP4_Strong BP7

The NM_003793.4(CTSF):​c.126C>G​(p.Pro42Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000869 in 1,151,196 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. P42P) has been classified as Benign.

• Frequency:
  • Genomes: not found (cov: 34)
  • Exomes 𝑓: 8.7e-7 (0 hom.)
• Consequence: CTSF NM_003793.4 synonymous
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0660
• 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: Labcorp Genetics (formerly Invitae), Orphanet, Ambry Genetics, Genomics England PanelApp

ACMG classification

Our verdict: Likely_benign. The variant received -3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BP7: Synonymous conserved (PhyloP=-0.066 with no splicing effect.

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.126C>G	p.Pro42Pro	synonymous	Exon 1 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.126C>G	p.Pro42Pro	synonymous	Exon 1 of 13	ENSP00000310832.5
	CTSF	ENST00000679347.1		c.126C>G	p.Pro42Pro	synonymous	Exon 1 of 13	ENSP00000503676.1
	CTSF	ENST00000677005.1		c.126C>G	p.Pro42Pro	synonymous	Exon 1 of 13	ENSP00000503238.1

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome AF: 8.69e-7 AC: 1 AN: 1151196 Hom.: 0 Cov.: 33 AF XY: 0.00000181 AC XY: 1 AN XY: 553060

African (AFR) AF: 0.00 AC: 0 AN: 23048

American (AMR) AF: 0.00 AC: 0 AN: 8488

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 15340

East Asian (EAS) AF: 0.00 AC: 0 AN: 26606

South Asian (SAS) AF: 0.00 AC: 0 AN: 35358

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 25914

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3162

European-Non Finnish (NFE) AF: 0.00000103 AC: 1 AN: 966266

Other (OTH) AF: 0.00 AC: 0 AN: 47014

GnomAD4 genome Cov.: 34

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	8.7
DANN	Benign	0.59
PhyloP100		-0.066
PromoterAI		0.12	Neutral

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs1044522; hg19: chr11-66335832;