11-66568077-A-G

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_003793.4(CTSF):c.219T>C(p.Gly73=) 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
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: 0.00700

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]

ACMG classification

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	UniProt
CTSF	NM_003793.4	c.219T>C	p.Gly73=	synonymous_variant	2/13	ENST00000310325.10
CTSF	XM_011545328.3	c.39T>C	p.Gly13=	synonymous_variant	2/13

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CTSF	ENST00000310325.10	c.219T>C	p.Gly73=	synonymous_variant	2/13	1	NM_003793.4	P3

Frequencies

GnomAD3 genomes AF: 0.609 AC: 92428 AN: 151892 Hom.: 29627 Cov.: 32

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

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.: 47 AF XY: 0.529 AC XY: 372950 AN XY: 705440

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.: 32 AF XY: 0.604 AC XY: 44878 AN XY: 74260

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:10

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Neuronal ceroid lipofuscinosis 13 Benign:4

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

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	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

Other links and lift over

dbSNP: rs1127894; hg19: chr11-66335548; COSMIC: COSV59747848; COSMIC: COSV59747848;