rs572846

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_003793.4(CTSF):c.1401T>C(p.Arg467=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.544 in 1,613,410 control chromosomes in the GnomAD database, including 244,359 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.61 ( 29741 hom., cov: 33)

Exomes 𝑓: 0.54 ( 214618 hom. )

Consequence

CTSF
NM_003793.4 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:10

Conservation

PhyloP100: -1.01

Variant links:

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.82).

BP6

Variant 11-66563987-A-G is Benign according to our data. Variant chr11-66563987-A-G is described in ClinVar as [Benign]. Clinvar id is 259168.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-66563987-A-G is described in Lovd as [Benign].

BP7

Synonymous conserved (PhyloP=-1.01 with no splicing effect.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.817 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CTSF	NM_003793.4 linkuse as main transcript	c.1401T>C	p.Arg467=	synonymous_variant	13/13	ENST00000310325.10
CTSF	XM_011545328.3 linkuse as main transcript	c.1221T>C	p.Arg407=	synonymous_variant	13/13

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CTSF	ENST00000310325.10 linkuse as main transcript	c.1401T>C	p.Arg467=	synonymous_variant	13/13	1	NM_003793.4	P3

Frequencies

GnomAD3 genomes

AF:

0.609

AC:

92535

AN:

151964

Hom.:

29684

Cov.:

show subpopulations

Gnomad AFR

AF:

0.824

Gnomad AMI

AF:

0.430

Gnomad AMR

AF:

0.446

Gnomad ASJ

AF:

0.528

Gnomad EAS

AF:

0.531

Gnomad SAS

AF:

0.395

Gnomad FIN

AF:

0.634

Gnomad MID

AF:

0.544

Gnomad NFE

AF:

0.539

Gnomad OTH

AF:

0.579

GnomAD3 exomes

AF:

0.521

AC:

130253

AN:

250108

Hom.:

35965

AF XY:

0.518

AC XY:

70156

AN XY:

135424

show subpopulations

Gnomad AFR exome

AF:

0.826

Gnomad AMR exome

AF:

0.327

Gnomad ASJ exome

AF:

0.544

Gnomad EAS exome

AF:

0.547

Gnomad SAS exome

AF:

0.396

Gnomad FIN exome

AF:

0.634

Gnomad NFE exome

AF:

0.543

Gnomad OTH exome

AF:

0.516

GnomAD4 exome

AF:

0.537

AC:

784612

AN:

1461328

Hom.:

214618

Cov.:

AF XY:

0.534

AC XY:

388057

AN XY:

726968

show subpopulations

Gnomad4 AFR exome

AF:

0.839

Gnomad4 AMR exome

AF:

0.342

Gnomad4 ASJ exome

AF:

0.537

Gnomad4 EAS exome

AF:

0.511

Gnomad4 SAS exome

AF:

0.402

Gnomad4 FIN exome

AF:

0.631

Gnomad4 NFE exome

AF:

0.542

Gnomad4 OTH exome

AF:

0.542

GnomAD4 genome

AF:

0.609

AC:

92641

AN:

152082

Hom.:

29741

Cov.:

AF XY:

0.605

AC XY:

44967

AN XY:

74340

show subpopulations

Gnomad4 AFR

AF:

0.825

Gnomad4 AMR

AF:

0.446

Gnomad4 ASJ

AF:

0.528

Gnomad4 EAS

AF:

0.531

Gnomad4 SAS

AF:

0.396

Gnomad4 FIN

AF:

0.634

Gnomad4 NFE

AF:

0.539

Gnomad4 OTH

AF:

0.575

Alfa

AF:

0.556

Hom.:

29139

Bravo

AF:

0.607

Asia WGS

AF:

0.491

AC:

1709

AN:

3478

EpiCase

AF:

0.541

EpiControl

AF:

0.540

ClinVar

Significance: Benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Neuronal ceroid lipofuscinosis 13

Benign:4

Benign, criteria provided, single submitter	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	Sep 21, 2015	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 30, 2024	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	Apr 22, 2016	- -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 30, 2021	- -

not provided

Benign:3

Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Apr 20, 2017	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 13, 2018	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Benign, no assertion criteria provided	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Oct 22, 2015	- -

not specified

Benign:2

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Dec 23, 2015	- -

Inborn genetic diseases

Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 08, 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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.82

Cadd

Benign

1.9

Dann

Benign

0.59

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over