rs28464796

chr11-66564618-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_003793.4(CTSF):c.1261C>T(p.Arg421Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00135 in 1,604,768 control chromosomes in the GnomAD database, including 29 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R421Q) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0068 (20 hom., cov: 33)
  • Exomes 𝑓: 0.00078 (9 hom.)
• Consequence: CTSF NM_003793.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 2.15

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.008280069).
• BP6: Variant 11-66564618-G-A is Benign according to our data. Variant chr11-66564618-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 376976.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00685 (1043/152312) while in subpopulation AFR AF= 0.0238 (991/41566). AF 95% confidence interval is 0.0226. There are 20 homozygotes in gnomad4. There are 499 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 20 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CTSF	NM_003793.4	c.1261C>T	p.Arg421Trp	missense_variant	11/13	ENST00000310325.10
CTSF	XM_011545328.3	c.1081C>T	p.Arg361Trp	missense_variant	11/13

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CTSF	ENST00000310325.10	c.1261C>T	p.Arg421Trp	missense_variant	11/13	1	NM_003793.4	P3

Frequencies

GnomAD3 genomes AF: 0.00685 AC: 1042 AN: 152194 Hom.: 20 Cov.: 33

Gnomad AFR AF: 0.0239

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00196

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000565

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000118

Gnomad OTH AF: 0.00382

GnomAD3 exomes AF: 0.00181 AC: 423 AN: 233326 Hom.: 1 AF XY: 0.00143 AC XY: 180 AN XY: 126290

Gnomad AFR exome AF: 0.0243

Gnomad AMR exome AF: 0.000982

Gnomad ASJ exome AF: 0.000103

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000345

Gnomad FIN exome AF: 0.000562

Gnomad NFE exome AF: 0.000143

Gnomad OTH exome AF: 0.000871

GnomAD4 exome AF: 0.000777 AC: 1129 AN: 1452456 Hom.: 9 Cov.: 32 AF XY: 0.000714 AC XY: 515 AN XY: 721704

Gnomad4 AFR exome AF: 0.0247

Gnomad4 AMR exome AF: 0.00146

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000254

Gnomad4 SAS exome AF: 0.0000707

Gnomad4 FIN exome AF: 0.000706

Gnomad4 NFE exome AF: 0.0000812

Gnomad4 OTH exome AF: 0.00163

GnomAD4 genome AF: 0.00685 AC: 1043 AN: 152312 Hom.: 20 Cov.: 33 AF XY: 0.00670 AC XY: 499 AN XY: 74480

Gnomad4 AFR AF: 0.0238

Gnomad4 AMR AF: 0.00196

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000565

Gnomad4 NFE AF: 0.000118

Gnomad4 OTH AF: 0.00378

Alfa AF: 0.00292 Hom.: 5

Bravo AF: 0.00745

ESP6500AA AF: 0.0218 AC: 96

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00212 AC: 257

Asia WGS AF: 0.00115 AC: 5 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Likely benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Aug 15, 2017	- -
Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Jan 12, 2017	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Aug 16, 2018	- -

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. -

Neuronal ceroid lipofuscinosis 13 Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 25, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.41	T
BayesDel_noAF	Benign	-0.34
Cadd	Uncertain	24
Dann	Uncertain	1.0
DEOGEN2	Uncertain	0.67	D
Eigen	Benign	-0.052
Eigen_PC	Benign	0.074
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Uncertain	0.94	D
MetaRNN	Benign	0.0083	T
MetaSVM	Benign	-0.70	T
MutationAssessor	Benign	0.97	L
MutationTaster	Benign	1.0	D
PrimateAI	Benign	0.35	T
PROVEAN	Pathogenic	-4.7	D
REVEL	Benign	0.21
Sift	Benign	0.11	T
Sift4G	Benign	0.14	T
Polyphen		0.20	B
Vest4		0.45
MVP		0.86
MPC		0.78
ClinPred		0.053	T
GERP RS		4.3
Varity_R		0.37
gMVP		0.76

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.11		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: rs28464796; hg19: chr11-66332089; COSMIC: COSV99072375; COSMIC: COSV99072375;