11-66568077-A-G

Position:

chr11-66568077-A-G

Variant summary

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

The NM_003793.4(CTSF):c.219T>C(p.Gly73Gly) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.54 in 1,575,052 control chromosomes in the GnomAD database, including 236,766 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. GQ73GPA?) has been classified as Pathogenic.

Frequency

Genomes: 𝑓 0.61 ( 29683 hom., cov: 32)

Exomes 𝑓: 0.53 ( 207083 hom. )

Consequence

CTSF
NM_003793.4 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:11

Conservation

PhyloP100: 0.00700

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:

CTSF (HGNC:):

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=-0.91).

BP6

Variant 11-66568077-A-G is Benign according to our data. Variant chr11-66568077-A-G is described in ClinVar as [Benign]. Clinvar id is 259169.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-66568077-A-G is described in Lovd as [Benign].

BP7

Synonymous conserved (PhyloP=0.007 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	Protein	UniProt
CTSF	NM_003793.4 linkuse as main transcript	c.219T>C	p.Gly73Gly	synonymous_variant	2/13	ENST00000310325.10	NP_003784.2	Q9UBX1
CTSF	XM_011545328.3 linkuse as main transcript	c.39T>C	p.Gly13Gly	synonymous_variant	2/13		XP_011543630.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CTSF	ENST00000310325.10 linkuse as main transcript	c.219T>C	p.Gly73Gly	synonymous_variant	2/13	1	NM_003793.4	ENSP00000310832.5		Q9UBX1

Frequencies

GnomAD3 genomes

AF:

0.609

AC:

92428

AN:

151892

Hom.:

29627

Cov.:

show subpopulations

Gnomad AFR

AF:

0.824

Gnomad AMI

AF:

0.428

Gnomad AMR

AF:

0.446

Gnomad ASJ

AF:

0.527

Gnomad EAS

AF:

0.530

Gnomad SAS

AF:

0.395

Gnomad FIN

AF:

0.630

Gnomad MID

AF:

0.544

Gnomad NFE

AF:

0.539

Gnomad OTH

AF:

0.580

GnomAD3 exomes

AF:

0.468

AC:

89503

AN:

191340

Hom.:

23907

AF XY:

0.467

AC XY:

49066

AN XY:

105016

show subpopulations

Gnomad AFR exome

AF:

0.792

Gnomad AMR exome

AF:

0.282

Gnomad ASJ exome

AF:

0.522

Gnomad EAS exome

AF:

0.493

Gnomad SAS exome

AF:

0.355

Gnomad FIN exome

AF:

0.595

Gnomad NFE exome

AF:

0.492

Gnomad OTH exome

AF:

0.477

GnomAD4 exome

AF:

0.533

AC:

757927

AN:

1423048

Hom.:

207083

Cov.:

AF XY:

0.529

AC XY:

372950

AN XY:

705440

show subpopulations

Gnomad4 AFR exome

AF:

0.838

Gnomad4 AMR exome

AF:

0.309

Gnomad4 ASJ exome

AF:

0.531

Gnomad4 EAS exome

AF:

0.495

Gnomad4 SAS exome

AF:

0.390

Gnomad4 FIN exome

AF:

0.617

Gnomad4 NFE exome

AF:

0.540

Gnomad4 OTH exome

AF:

0.537

GnomAD4 genome

AF:

0.609

AC:

92530

AN:

152004

Hom.:

29683

Cov.:

AF XY:

0.604

AC XY:

44878

AN XY:

74260

show subpopulations

Gnomad4 AFR

AF:

0.824

Gnomad4 AMR

AF:

0.446

Gnomad4 ASJ

AF:

0.527

Gnomad4 EAS

AF:

0.530

Gnomad4 SAS

AF:

0.395

Gnomad4 FIN

AF:

0.630

Gnomad4 NFE

AF:

0.539

Gnomad4 OTH

AF:

0.575

Alfa

AF:

0.548

Hom.:

8814

Bravo

AF:

0.606

Asia WGS

AF:

0.486

AC:

1685

AN:

3470

ClinVar

Significance: Benign

Submissions summary: Benign:11

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:4

Benign, no assertion criteria provided	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Oct 22, 2015	- -
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, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Apr 20, 2017	- -

Neuronal ceroid lipofuscinosis 13

Benign:4

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 30, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	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	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	Sep 21, 2015	- -

not specified

Benign:2

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Dec 03, 2021	- -

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

-0.91

CADD

Benign

8.4

DANN

Benign

0.61

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

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