chr11-66564618-G-A

Variant names:

• chr11-66564618-G-A
• rs28464796
• NM_003793.4:c.1261C>T

Variant summary

Our verdict is Benign. The variant received -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. 13/21 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
• Publications: 4 publications found

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: Orphanet, Genomics England PanelApp, Labcorp Genetics (formerly Invitae), Ambry Genetics

ACMG classification

Our verdict: Benign. The variant received -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 Benign/Likely_benign. ClinVar VariationId 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 the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 20 AR,Unknown gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_003793.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CTSF	NM_003793.4	MANE Select	c.1261C>T	p.Arg421Trp	missense	Exon 11 of 13	NP_003784.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CTSF	ENST00000310325.10	TSL:1 MANE Select	c.1261C>T	p.Arg421Trp	missense	Exon 11 of 13	ENSP00000310832.5	Q9UBX1
	CTSF	ENST00000679347.1		c.1261C>T	p.Arg421Trp	missense	Exon 11 of 13	ENSP00000503676.1	A0A7I2YQH8
	CTSF	ENST00000677005.1		c.1261C>T	p.Arg421Trp	missense	Exon 11 of 13	ENSP00000503238.1	A0A7I2V313

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

GnomAD2 exomes AF: 0.00181 AC: 423 AN: 233326 AF XY: 0.00143

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 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

African (AFR) AF: 0.0247 AC: 825 AN: 33370

American (AMR) AF: 0.00146 AC: 63 AN: 43024

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25930

East Asian (EAS) AF: 0.0000254 AC: 1 AN: 39348

South Asian (SAS) AF: 0.0000707 AC: 6 AN: 84820

European-Finnish (FIN) AF: 0.000706 AC: 37 AN: 52418

Middle Eastern (MID) AF: 0.00158 AC: 9 AN: 5694

European-Non Finnish (NFE) AF: 0.0000812 AC: 90 AN: 1107840

Other (OTH) AF: 0.00163 AC: 98 AN: 60012

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

African (AFR) AF: 0.0238 AC: 991 AN: 41566

American (AMR) AF: 0.00196 AC: 30 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5176

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.000565 AC: 6 AN: 10620

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000118 AC: 8 AN: 68026

Other (OTH) AF: 0.00378 AC: 8 AN: 2116

Alfa AF: 0.00427 Hom.: 10

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

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	1	Inborn genetic diseases (1)
-	-	1	Neuronal ceroid lipofuscinosis 13 (1)

Computational scores

Source: dbNSFP v4.9

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
PhyloP100		2.1
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
Mutation Taster		=83/17	polymorphism

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

Other links and lift over

dbSNP: rs28464796; hg19: chr11-66332089; COSMIC: COSV99072375; COSMIC: COSV99072375;