chr11-66563698-C-T

Position:

• chr11-66563698-C-T

Variant summary

Our verdict is Benign. Variant got -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

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]

ACMG classification

Verdict is Benign. Variant got -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 id 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CTSF	NM_003793.4	c.*235G>A		3_prime_UTR_variant	13/13	ENST00000310325.10
CTSF	XM_011545328.3	c.*235G>A		3_prime_UTR_variant	13/13

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CTSF	ENST00000310325.10	c.*235G>A		3_prime_UTR_variant	13/13	1	NM_003793.4	P3

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

Gnomad4 AFR exome AF: 0.0123

Gnomad4 AMR exome AF: 0.0646

Gnomad4 ASJ exome AF: 0.0354

Gnomad4 EAS exome AF: 0.106

Gnomad4 SAS exome AF: 0.0807

Gnomad4 FIN exome AF: 0.202

Gnomad4 NFE exome AF: 0.0796

Gnomad4 OTH exome AF: 0.0749

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

Gnomad4 AFR AF: 0.0129

Gnomad4 AMR AF: 0.0708

Gnomad4 ASJ AF: 0.0340

Gnomad4 EAS AF: 0.112

Gnomad4 SAS AF: 0.0875

Gnomad4 FIN AF: 0.218

Gnomad4 NFE AF: 0.0805

Gnomad4 OTH AF: 0.0506

Alfa AF: 0.0735 Hom.: 309

Bravo AF: 0.0554

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 17, 2018	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	7.5
DANN	Benign	0.33
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0

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

Publications

LitVar

Other links and lift over

dbSNP: rs13897; hg19: chr11-66331169;