rs572846

Variant names:

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_003793.4(CTSF):c.1401T>C(p.Arg467Arg) 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:11

Conservation

PhyloP100: -1.01

Publications

32 publications found

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 Gene-Disease associations (from GenCC):

adult neuronal ceroid lipofuscinosis
Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
neuronal ceroid lipofuscinosis 13
Inheritance: AR, Unknown Classification: DEFINITIVE, STRONG, SUPPORTIVE, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Orphanet, Ambry Genetics, Genomics England PanelApp

CTSF links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -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 VariationId is 259168.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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 rank	MANE	Protein	UniProt
CTSF	NM_003793.4 link	c.1401T>C	p.Arg467Arg	synonymous_variant	Exon 13 of 13	ENST00000310325.10	NP_003784.2	Q9UBX1
CTSF	XM_011545328.3 link	c.1221T>C	p.Arg407Arg	synonymous_variant	Exon 13 of 13		XP_011543630.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CTSF	ENST00000310325.10 link	c.1401T>C	p.Arg467Arg	synonymous_variant	Exon 13 of 13	1	NM_003793.4	ENSP00000310832.5		Q9UBX1

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

GnomAD2 exomes

AF:

0.521

AC:

130253

AN:

250108

AF XY:

0.518

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 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

African (AFR)

AF:

0.839

AC:

28084

AN:

33474

American (AMR)

AF:

0.342

AC:

15267

AN:

44704

Ashkenazi Jewish (ASJ)

AF:

0.537

AC:

14033

AN:

26132

East Asian (EAS)

AF:

0.511

AC:

20298

AN:

39688

South Asian (SAS)

AF:

0.402

AC:

34647

AN:

86234

European-Finnish (FIN)

AF:

0.631

AC:

33496

AN:

53090

Middle Eastern (MID)

AF:

0.516

AC:

2955

AN:

5722

European-Non Finnish (NFE)

AF:

0.542

AC:

603137

AN:

1111908

Other (OTH)

AF:

0.542

AC:

32695

AN:

60376

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.470

Heterozygous variant carriers

24159

48318

72478

96637

120796

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

17066

34132

51198

68264

85330

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.609

AC:

92641

AN:

152082

Hom.:

29741

Cov.:

AF XY:

0.605

AC XY:

44967

AN XY:

74340

show subpopulations

African (AFR)

AF:

0.825

AC:

34214

AN:

41490

American (AMR)

AF:

0.446

AC:

6821

AN:

15292

Ashkenazi Jewish (ASJ)

AF:

0.528

AC:

1830

AN:

3468

East Asian (EAS)

AF:

0.531

AC:

2738

AN:

5160

South Asian (SAS)

AF:

0.396

AC:

1910

AN:

4826

European-Finnish (FIN)

AF:

0.634

AC:

6710

AN:

10578

Middle Eastern (MID)

AF:

0.548

AC:

161

AN:

294

European-Non Finnish (NFE)

AF:

0.539

AC:

36657

AN:

67960

Other (OTH)

AF:

0.575

AC:

1210

AN:

2106

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

1766

3532

5299

7065

8831

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

746

1492

2238

2984

3730

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.573

Hom.:

37938

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:11

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Neuronal ceroid lipofuscinosis 13

Benign:4

Apr 22, 2016

Genome Diagnostics Laboratory, Amsterdam University Medical Center

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Sep 21, 2015

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jul 30, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:4

Oct 22, 2015

Mayo Clinic Laboratories, Mayo Clinic

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Jun 13, 2018

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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. -

Apr 20, 2017

Athena Diagnostics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

not specified

Benign:2

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Dec 23, 2015

Eurofins Ntd Llc (ga)

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Inborn genetic diseases

Benign:1

Jan 08, 2016

Ambry Genetics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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

(source)

DANN

Benign

0.59

PhyloP100

-1.0

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over