NM_003793.4:c.126C>T

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.126C>T(p.Pro42Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.236 in 1,303,162 control chromosomes in the GnomAD database, including 36,849 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.23 ( 3919 hom., cov: 34)

Exomes 𝑓: 0.24 ( 32930 hom. )

Consequence

CTSF
NM_003793.4 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:9

Conservation

PhyloP100: -0.0660

Publications

14 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=-0.8).

BP6

Variant 11-66568361-G-A is Benign according to our data. Variant chr11-66568361-G-A is described in ClinVar as Benign. ClinVar VariationId is 259166.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-0.066 with no splicing effect.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.233 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CTSF	NM_003793.4 link	c.126C>T	p.Pro42Pro	synonymous_variant	Exon 1 of 13	ENST00000310325.10	NP_003784.2	Q9UBX1
CTSF	XM_011545328.3 link	c.-158C>T		5_prime_UTR_variant	Exon 1 of 13		XP_011543630.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CTSF	ENST00000310325.10 link	c.126C>T	p.Pro42Pro	synonymous_variant	Exon 1 of 13	1	NM_003793.4	ENSP00000310832.5		Q9UBX1

Frequencies

GnomAD3 genomes

AF:

0.226

AC:

34276

AN:

151948

Hom.:

3920

Cov.:

show subpopulations

Gnomad AFR

AF:

0.232

Gnomad AMI

AF:

0.168

Gnomad AMR

AF:

0.194

Gnomad ASJ

AF:

0.293

Gnomad EAS

AF:

0.244

Gnomad SAS

AF:

0.129

Gnomad FIN

AF:

0.197

Gnomad MID

AF:

0.309

Gnomad NFE

AF:

0.235

Gnomad OTH

AF:

0.251

GnomAD2 exomes

AF:

0.222

AC:

125

AN:

562

AF XY:

0.212

show subpopulations

Gnomad AFR exome

AF:

0.100

Gnomad AMR exome

AF:

0.227

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.219

Gnomad FIN exome

AF:

0.143

Gnomad NFE exome

AF:

0.236

Gnomad OTH exome

AF:

0.0833

GnomAD4 exome

AF:

0.237

AC:

273315

AN:

1151106

Hom.:

32930

Cov.:

AF XY:

0.237

AC XY:

131066

AN XY:

553022

show subpopulations

African (AFR)

AF:

0.232

AC:

5342

AN:

23046

American (AMR)

AF:

0.177

AC:

1501

AN:

8486

Ashkenazi Jewish (ASJ)

AF:

0.289

AC:

4426

AN:

15338

East Asian (EAS)

AF:

0.234

AC:

6233

AN:

26604

South Asian (SAS)

AF:

0.124

AC:

4377

AN:

35354

European-Finnish (FIN)

AF:

0.206

AC:

5340

AN:

25906

Middle Eastern (MID)

AF:

0.272

AC:

860

AN:

3160

European-Non Finnish (NFE)

AF:

0.242

AC:

234099

AN:

966202

Other (OTH)

AF:

0.237

AC:

11137

AN:

47010

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.489

Heterozygous variant carriers

12788

25576

38365

51153

63941

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

8786

17572

26358

35144

43930

<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:

0.225

AC:

34277

AN:

152056

Hom.:

3919

Cov.:

AF XY:

0.221

AC XY:

16450

AN XY:

74340

show subpopulations

African (AFR)

AF:

0.232

AC:

9621

AN:

41516

American (AMR)

AF:

0.194

AC:

2964

AN:

15280

Ashkenazi Jewish (ASJ)

AF:

0.293

AC:

1016

AN:

3470

East Asian (EAS)

AF:

0.245

AC:

1261

AN:

5156

South Asian (SAS)

AF:

0.129

AC:

625

AN:

4830

European-Finnish (FIN)

AF:

0.197

AC:

2077

AN:

10552

Middle Eastern (MID)

AF:

0.305

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.235

AC:

15941

AN:

67938

Other (OTH)

AF:

0.251

AC:

530

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

1440

2880

4320

5760

7200

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

352

704

1056

1408

1760

<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:

0.234

Hom.:

518

Bravo

AF:

0.229

Asia WGS

AF:

0.184

AC:

636

AN:

3446

ClinVar

Significance: Benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:4

Dec 16, 2015

Mayo Clinic Laboratories, Mayo Clinic

Significance:Likely 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

- -

Neuronal ceroid lipofuscinosis 13

Benign:3

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

- -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

May 09, 2016

Genome Diagnostics Laboratory, Amsterdam University Medical Center

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

not specified

Benign:1

PreventionGenetics, part of Exact Sciences

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

-0.80

CADD

Benign

(source)

DANN

Benign

0.82

PhyloP100

-0.066

PromoterAI

0.051

Neutral

(source)

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

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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