rs78871927

Positions:

• chr11-66566172-G-A

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.722-5C>T variant causes a splice region, splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0772 in 1,613,818 control chromosomes in the GnomAD database, including 6,046 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.070 (647 hom., cov: 32)
  • Exomes 𝑓: 0.078 (5399 hom.)
• Consequence: CTSF NM_003793.4 splice_region, splice_polypyrimidine_tract, intron
• Scores: Splicing: ADA: 0.00001609
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 0.00100

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=-0.83).
• BP6: Variant 11-66566172-G-A is Benign according to our data. Variant chr11-66566172-G-A is described in ClinVar as [Benign]. Clinvar id is 259171.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-66566172-G-A is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.105 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CTSF	NM_003793.4	c.722-5C>T		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		ENST00000310325.10
CTSF	XM_011545328.3	c.542-5C>T		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CTSF	ENST00000310325.10	c.722-5C>T		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		1	NM_003793.4	P3

Frequencies

GnomAD3 genomes AF: 0.0700 AC: 10633 AN: 152004 Hom.: 642 Cov.: 32

Gnomad AFR AF: 0.0130

Gnomad AMI AF: 0.0373

Gnomad AMR AF: 0.0700

Gnomad ASJ AF: 0.0340

Gnomad EAS AF: 0.112

Gnomad SAS AF: 0.0870

Gnomad FIN AF: 0.218

Gnomad MID AF: 0.0190

Gnomad NFE AF: 0.0803

Gnomad OTH AF: 0.0523

GnomAD3 exomes AF: 0.0871 AC: 21863 AN: 251142 Hom.: 1308 AF XY: 0.0877 AC XY: 11897 AN XY: 135730

Gnomad AFR exome AF: 0.0112

Gnomad AMR exome AF: 0.0636

Gnomad ASJ exome AF: 0.0365

Gnomad EAS exome AF: 0.109

Gnomad SAS exome AF: 0.0849

Gnomad FIN exome AF: 0.212

Gnomad NFE exome AF: 0.0831

Gnomad OTH exome AF: 0.0815

GnomAD4 exome AF: 0.0779 AC: 113929 AN: 1461696 Hom.: 5399 Cov.: 35 AF XY: 0.0786 AC XY: 57124 AN XY: 727132

Gnomad4 AFR exome AF: 0.0105

Gnomad4 AMR exome AF: 0.0639

Gnomad4 ASJ exome AF: 0.0372

Gnomad4 EAS exome AF: 0.107

Gnomad4 SAS exome AF: 0.0823

Gnomad4 FIN exome AF: 0.206

Gnomad4 NFE exome AF: 0.0745

Gnomad4 OTH exome AF: 0.0727

GnomAD4 genome AF: 0.0700 AC: 10649 AN: 152122 Hom.: 647 Cov.: 32 AF XY: 0.0766 AC XY: 5692 AN XY: 74330

Gnomad4 AFR AF: 0.0130

Gnomad4 AMR AF: 0.0709

Gnomad4 ASJ AF: 0.0340

Gnomad4 EAS AF: 0.112

Gnomad4 SAS AF: 0.0879

Gnomad4 FIN AF: 0.218

Gnomad4 NFE AF: 0.0803

Gnomad4 OTH AF: 0.0503

Alfa AF: 0.0698 Hom.: 251

Bravo AF: 0.0553

Asia WGS AF: 0.121 AC: 420 AN: 3478

EpiCase AF: 0.0706

EpiControl AF: 0.0696

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Benign, no assertion criteria provided	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Oct 26, 2015	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Apr 20, 2017	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 17, 2018	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

-

- -

Inborn genetic diseases Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 02, 2016

This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Neuronal ceroid lipofuscinosis 13 Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 30, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	2.3
DANN	Benign	0.78

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000016
dbscSNV1_RF	Benign	0.0020
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: rs78871927; hg19: chr11-66333643; COSMIC: COSV59747585; COSMIC: COSV59747585;