11-66566172-G-A

Position:

chr11-66566172-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

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:7

Conservation

PhyloP100: 0.00100

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 -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	Protein	UniProt
CTSF	NM_003793.4 linkuse as main transcript	c.722-5C>T		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		ENST00000310325.10	NP_003784.2
CTSF	XM_011545328.3 linkuse as main transcript	c.542-5C>T		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant			XP_011543630.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CTSF	ENST00000310325.10 linkuse as main transcript	c.722-5C>T		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		1	NM_003793.4	ENSP00000310832	P3

Frequencies

GnomAD3 genomes

AF:

0.0700

AC:

10633

AN:

152004

Hom.:

642

Cov.:

show subpopulations

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

show subpopulations

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.:

AF XY:

0.0786

AC XY:

57124

AN XY:

727132

show subpopulations

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.:

AF XY:

0.0766

AC XY:

5692

AN XY:

74330

show subpopulations

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:7

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 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	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

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

Labcorp Genetics (formerly Invitae), Labcorp

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

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