11-66567837-T-C

Variant names:

• chr11-66567837-T-C
• rs2242663
• NM_003793.4:c.312+147A>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_003793.4(CTSF):​c.312+147A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.23 in 1,359,172 control chromosomes in the GnomAD database, including 37,050 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.23 (3911 hom., cov: 32)
  • Exomes 𝑓: 0.23 (33139 hom.)
• Consequence: CTSF NM_003793.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.632
• Publications: 48 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: Labcorp Genetics (formerly Invitae), Orphanet, Ambry Genetics, Genomics England PanelApp

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.88).
• BP6: Variant 11-66567837-T-C is Benign according to our data. Variant chr11-66567837-T-C is described in ClinVar as Benign. ClinVar VariationId is 1271666.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.232 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CTSF	NM_003793.4	c.312+147A>G		intron_variant	Intron 2 of 12	ENST00000310325.10	NP_003784.2
CTSF	XM_011545328.3	c.132+147A>G		intron_variant	Intron 2 of 12		XP_011543630.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CTSF	ENST00000310325.10	c.312+147A>G		intron_variant	Intron 2 of 12	1	NM_003793.4	ENSP00000310832.5

Frequencies

GnomAD3 genomes AF: 0.226 AC: 34287 AN: 151988 Hom.: 3912 Cov.: 32

Gnomad AFR AF: 0.232

Gnomad AMI AF: 0.168

Gnomad AMR AF: 0.194

Gnomad ASJ AF: 0.293

Gnomad EAS AF: 0.242

Gnomad SAS AF: 0.130

Gnomad FIN AF: 0.197

Gnomad MID AF: 0.303

Gnomad NFE AF: 0.235

Gnomad OTH AF: 0.251

GnomAD4 exome AF: 0.230 AC: 277955 AN: 1207066 Hom.: 33139 Cov.: 18 AF XY: 0.228 AC XY: 135366 AN XY: 593636

African (AFR) AF: 0.230 AC: 6142 AN: 26716

American (AMR) AF: 0.164 AC: 3710 AN: 22618

Ashkenazi Jewish (ASJ) AF: 0.284 AC: 5245 AN: 18500

East Asian (EAS) AF: 0.240 AC: 8648 AN: 36020

South Asian (SAS) AF: 0.119 AC: 7602 AN: 64002

European-Finnish (FIN) AF: 0.202 AC: 8824 AN: 43770

Middle Eastern (MID) AF: 0.278 AC: 1403 AN: 5044

European-Non Finnish (NFE) AF: 0.239 AC: 224507 AN: 939468

Other (OTH) AF: 0.233 AC: 11874 AN: 50928

GnomAD4 genome AF: 0.225 AC: 34289 AN: 152106 Hom.: 3911 Cov.: 32 AF XY: 0.221 AC XY: 16439 AN XY: 74352

African (AFR) AF: 0.232 AC: 9622 AN: 41512

American (AMR) AF: 0.194 AC: 2966 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.293 AC: 1016 AN: 3468

East Asian (EAS) AF: 0.243 AC: 1247 AN: 5142

South Asian (SAS) AF: 0.130 AC: 626 AN: 4826

European-Finnish (FIN) AF: 0.197 AC: 2082 AN: 10578

Middle Eastern (MID) AF: 0.298 AC: 87 AN: 292

European-Non Finnish (NFE) AF: 0.235 AC: 15961 AN: 67972

Other (OTH) AF: 0.251 AC: 529 AN: 2108

Alfa AF: 0.240 Hom.: 6368

Bravo AF: 0.229

Asia WGS AF: 0.186 AC: 649 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Jun 28, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	2.3
DANN	Benign	0.40
PhyloP100		-0.63
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs2242663; hg19: chr11-66335308; COSMIC: COSV59750894; COSMIC: COSV59750894;