11-66563698-C-T

Variant names:

• chr11-66563698-C-T
• rs13897
• NM_003793.4:c.*235G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_003793.4(CTSF):​c.*235G>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0813 in 602,612 control chromosomes in the GnomAD database, including 2,736 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.070 (655 hom., cov: 32)
  • Exomes 𝑓: 0.085 (2081 hom.)
• Consequence: CTSF NM_003793.4 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.0440
• Publications: 21 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: Unknown, AR Classification: DEFINITIVE, STRONG, SUPPORTIVE, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Genomics England PanelApp, Ambry Genetics, Orphanet

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.85).
• BP6: Variant 11-66563698-C-T is Benign according to our data. Variant chr11-66563698-C-T is described in ClinVar as Benign. ClinVar VariationId is 1289607.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.104 is higher than 0.05.

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.*235G>A		3_prime_UTR	Exon 13 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.*235G>A		3_prime_UTR	Exon 13 of 13	ENSP00000310832.5	Q9UBX1
	CTSF	ENST00000679347.1		c.*267G>A		3_prime_UTR	Exon 13 of 13	ENSP00000503676.1	A0A7I2YQH8
	CTSF	ENST00000677005.1		c.*267G>A		3_prime_UTR	Exon 13 of 13	ENSP00000503238.1	A0A7I2V313

Frequencies

GnomAD3 genomes AF: 0.0700 AC: 10650 AN: 152140 Hom.: 650 Cov.: 32

Gnomad AFR AF: 0.0129

Gnomad AMI AF: 0.0373

Gnomad AMR AF: 0.0700

Gnomad ASJ AF: 0.0340

Gnomad EAS AF: 0.111

Gnomad SAS AF: 0.0866

Gnomad FIN AF: 0.218

Gnomad MID AF: 0.0190

Gnomad NFE AF: 0.0805

Gnomad OTH AF: 0.0526

GnomAD4 exome AF: 0.0851 AC: 38340 AN: 450354 Hom.: 2081 Cov.: 5 AF XY: 0.0844 AC XY: 19840 AN XY: 234958

African (AFR) AF: 0.0123 AC: 153 AN: 12480

American (AMR) AF: 0.0646 AC: 1200 AN: 18562

Ashkenazi Jewish (ASJ) AF: 0.0354 AC: 481 AN: 13598

East Asian (EAS) AF: 0.106 AC: 3288 AN: 30934

South Asian (SAS) AF: 0.0807 AC: 3497 AN: 43356

European-Finnish (FIN) AF: 0.202 AC: 5904 AN: 29256

Middle Eastern (MID) AF: 0.0271 AC: 53 AN: 1956

European-Non Finnish (NFE) AF: 0.0796 AC: 21812 AN: 274150

Other (OTH) AF: 0.0749 AC: 1952 AN: 26062

GnomAD4 genome AF: 0.0701 AC: 10666 AN: 152258 Hom.: 655 Cov.: 32 AF XY: 0.0767 AC XY: 5708 AN XY: 74450

African (AFR) AF: 0.0129 AC: 536 AN: 41586

American (AMR) AF: 0.0708 AC: 1083 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.0340 AC: 118 AN: 3472

East Asian (EAS) AF: 0.112 AC: 578 AN: 5180

South Asian (SAS) AF: 0.0875 AC: 421 AN: 4814

European-Finnish (FIN) AF: 0.218 AC: 2309 AN: 10604

Middle Eastern (MID) AF: 0.0204 AC: 6 AN: 294

European-Non Finnish (NFE) AF: 0.0805 AC: 5474 AN: 67996

Other (OTH) AF: 0.0506 AC: 107 AN: 2114

Alfa AF: 0.0757 Hom.: 531

Bravo AF: 0.0554

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	7.5
DANN	Benign	0.33
PhyloP100		-0.044
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Mutation Taster		=100/0	polymorphism (auto)

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: rs13897; hg19: chr11-66331169;