rs78871927

Variant names:

• chr11-66566172-G-A
• rs78871927
• NM_003793.4:c.722-5C>T

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.722-5C>T variant causes a splice region, 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, intron
• Scores: Splicing: ADA: 0.00001609
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 0.00100
• Publications: 11 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=-0.83).
• BP6: Variant 11-66566172-G-A is Benign according to our data. Variant chr11-66566172-G-A is described in ClinVar as Benign. ClinVar VariationId is 259171.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.105 is higher than 0.05.

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.722-5C>T		splice_region intron	N/A	NP_003784.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CTSF	ENST00000310325.10	TSL:1 MANE Select	c.722-5C>T		splice_region intron	N/A	ENSP00000310832.5
	CTSF	ENST00000679347.1		c.722-5C>T		splice_region intron	N/A	ENSP00000503676.1
	CTSF	ENST00000677005.1		c.722-5C>T		splice_region intron	N/A	ENSP00000503238.1

Frequencies

GnomAD3 genomes AF: 0.0700 AC: 10633 AN: 152004 Hom.: 642 Cov.: 32

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

GnomAD2 exomes AF: 0.0871 AC: 21863 AN: 251142 AF XY: 0.0877

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 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.: 35 AF XY: 0.0786 AC XY: 57124 AN XY: 727132

African (AFR) AF: 0.0105 AC: 353 AN: 33478

American (AMR) AF: 0.0639 AC: 2856 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.0372 AC: 973 AN: 26130

East Asian (EAS) AF: 0.107 AC: 4250 AN: 39698

South Asian (SAS) AF: 0.0823 AC: 7094 AN: 86240

European-Finnish (FIN) AF: 0.206 AC: 10987 AN: 53334

Middle Eastern (MID) AF: 0.0234 AC: 135 AN: 5768

European-Non Finnish (NFE) AF: 0.0745 AC: 82890 AN: 1111944

Other (OTH) AF: 0.0727 AC: 4391 AN: 60382

GnomAD4 genome AF: 0.0700 AC: 10649 AN: 152122 Hom.: 647 Cov.: 32 AF XY: 0.0766 AC XY: 5692 AN XY: 74330

African (AFR) AF: 0.0130 AC: 538 AN: 41506

American (AMR) AF: 0.0709 AC: 1083 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.0340 AC: 118 AN: 3470

East Asian (EAS) AF: 0.112 AC: 580 AN: 5166

South Asian (SAS) AF: 0.0879 AC: 423 AN: 4814

European-Finnish (FIN) AF: 0.218 AC: 2302 AN: 10562

Middle Eastern (MID) AF: 0.0204 AC: 6 AN: 294

European-Non Finnish (NFE) AF: 0.0803 AC: 5459 AN: 68008

Other (OTH) AF: 0.0503 AC: 106 AN: 2106

Alfa AF: 0.0689 Hom.: 259

Bravo AF: 0.0553

Asia WGS AF: 0.121 AC: 420 AN: 3478

EpiCase AF: 0.0706

EpiControl AF: 0.0696

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not provided (4)
-	-	1	Inborn genetic diseases (1)
-	-	1	Neuronal ceroid lipofuscinosis 13 (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	2.3
DANN	Benign	0.78
PhyloP100		0.0010
Mutation Taster		=99/1	polymorphism (auto)

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

Other links and lift over

dbSNP: rs78871927; hg19: chr11-66333643; COSMIC: COSV59747585; COSMIC: COSV59747585;