11-66563714-TACC-T

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP6_Moderate BS1 BS2

The NM_003793.4(CTSF):c.*216_*218del variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0176 in 616,354 control chromosomes in the GnomAD database, including 113 homozygotes. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.015 (20 hom., cov: 32)
  • Exomes 𝑓: 0.018 (93 hom.)
• Consequence: CTSF NM_003793.4 3_prime_UTR
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 1.90

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 -10 ACMG points.

• BP6: Variant 11-66563714-TACC-T is Benign according to our data. Variant chr11-66563714-TACC-T is described in ClinVar as [Likely_benign]. Clinvar id is 1185770.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0151 (2306/152306) while in subpopulation NFE AF= 0.0238 (1617/68020). AF 95% confidence interval is 0.0228. There are 20 homozygotes in gnomad4. There are 1078 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 20 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CTSF	NM_003793.4	c.*216_*218del		3_prime_UTR_variant	13/13	ENST00000310325.10
CTSF	XM_011545328.3	c.*216_*218del		3_prime_UTR_variant	13/13

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CTSF	ENST00000310325.10	c.*216_*218del		3_prime_UTR_variant	13/13	1	NM_003793.4	P3

Frequencies

GnomAD3 genomes AF: 0.0152 AC: 2310 AN: 152188 Hom.: 20 Cov.: 32

Gnomad AFR AF: 0.00506

Gnomad AMI AF: 0.0121

Gnomad AMR AF: 0.0168

Gnomad ASJ AF: 0.00980

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.00166

Gnomad FIN AF: 0.0112

Gnomad MID AF: 0.0190

Gnomad NFE AF: 0.0238

Gnomad OTH AF: 0.0211

GnomAD4 exome AF: 0.0185 AC: 8566 AN: 464048 Hom.: 93 AF XY: 0.0172 AC XY: 4168 AN XY: 242490

Gnomad4 AFR exome AF: 0.00410

Gnomad4 AMR exome AF: 0.0179

Gnomad4 ASJ exome AF: 0.0101

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00139

Gnomad4 FIN exome AF: 0.00990

Gnomad4 NFE exome AF: 0.0250

Gnomad4 OTH exome AF: 0.0201

GnomAD4 genome AF: 0.0151 AC: 2306 AN: 152306 Hom.: 20 Cov.: 32 AF XY: 0.0145 AC XY: 1078 AN XY: 74472

Gnomad4 AFR AF: 0.00505

Gnomad4 AMR AF: 0.0167

Gnomad4 ASJ AF: 0.00980

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00166

Gnomad4 FIN AF: 0.0112

Gnomad4 NFE AF: 0.0238

Gnomad4 OTH AF: 0.0208

Alfa AF: 0.0186 Hom.: 4

Bravo AF: 0.0161

Asia WGS AF: 0.00318 AC: 11 AN: 3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

GeneDx

Jul 21, 2018

- -

Computational scores

Source: dbNSFP v4.3

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: rs201073320; hg19: chr11-66331185;