rs1044522

Variant names:

• chr11-66568361-G-A
• rs1044522
• NM_003793.4:c.126C>T

Your query was ambiguous. Multiple possible variants found:

• chr11-66568361-G-A
• chr11-66568361-G-C

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_003793.4(CTSF):​c.126C>T​(p.Pro42Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.236 in 1,303,162 control chromosomes in the GnomAD database, including 36,849 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.23 (3919 hom., cov: 34)
  • Exomes 𝑓: 0.24 (32930 hom.)
• Consequence: CTSF NM_003793.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: -0.0660
• Publications: 14 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.8).
• BP6: Variant 11-66568361-G-A is Benign according to our data. Variant chr11-66568361-G-A is described in ClinVar as Benign. ClinVar VariationId is 259166.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.066 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.233 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.126C>T	p.Pro42Pro	synonymous	Exon 1 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.126C>T	p.Pro42Pro	synonymous	Exon 1 of 13	ENSP00000310832.5
	CTSF	ENST00000679347.1		c.126C>T	p.Pro42Pro	synonymous	Exon 1 of 13	ENSP00000503676.1
	CTSF	ENST00000677005.1		c.126C>T	p.Pro42Pro	synonymous	Exon 1 of 13	ENSP00000503238.1

Frequencies

GnomAD3 genomes AF: 0.226 AC: 34276 AN: 151948 Hom.: 3920 Cov.: 34

Gnomad AFR AF: 0.232

Gnomad AMI AF: 0.168

Gnomad AMR AF: 0.194

Gnomad ASJ AF: 0.293

Gnomad EAS AF: 0.244

Gnomad SAS AF: 0.129

Gnomad FIN AF: 0.197

Gnomad MID AF: 0.309

Gnomad NFE AF: 0.235

Gnomad OTH AF: 0.251

GnomAD2 exomes AF: 0.222 AC: 125 AN: 562 AF XY: 0.212

Gnomad AFR exome AF: 0.100

Gnomad AMR exome AF: 0.227

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.219

Gnomad FIN exome AF: 0.143

Gnomad NFE exome AF: 0.236

Gnomad OTH exome AF: 0.0833

GnomAD4 exome AF: 0.237 AC: 273315 AN: 1151106 Hom.: 32930 Cov.: 33 AF XY: 0.237 AC XY: 131066 AN XY: 553022

African (AFR) AF: 0.232 AC: 5342 AN: 23046

American (AMR) AF: 0.177 AC: 1501 AN: 8486

Ashkenazi Jewish (ASJ) AF: 0.289 AC: 4426 AN: 15338

East Asian (EAS) AF: 0.234 AC: 6233 AN: 26604

South Asian (SAS) AF: 0.124 AC: 4377 AN: 35354

European-Finnish (FIN) AF: 0.206 AC: 5340 AN: 25906

Middle Eastern (MID) AF: 0.272 AC: 860 AN: 3160

European-Non Finnish (NFE) AF: 0.242 AC: 234099 AN: 966202

Other (OTH) AF: 0.237 AC: 11137 AN: 47010

GnomAD4 genome AF: 0.225 AC: 34277 AN: 152056 Hom.: 3919 Cov.: 34 AF XY: 0.221 AC XY: 16450 AN XY: 74340

African (AFR) AF: 0.232 AC: 9621 AN: 41516

American (AMR) AF: 0.194 AC: 2964 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.293 AC: 1016 AN: 3470

East Asian (EAS) AF: 0.245 AC: 1261 AN: 5156

South Asian (SAS) AF: 0.129 AC: 625 AN: 4830

European-Finnish (FIN) AF: 0.197 AC: 2077 AN: 10552

Middle Eastern (MID) AF: 0.305 AC: 89 AN: 292

European-Non Finnish (NFE) AF: 0.235 AC: 15941 AN: 67938

Other (OTH) AF: 0.251 AC: 530 AN: 2112

Alfa AF: 0.234 Hom.: 518

Bravo AF: 0.229

Asia WGS AF: 0.184 AC: 636 AN: 3446

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not provided (4)
-	-	3	Neuronal ceroid lipofuscinosis 13 (3)
-	-	1	Inborn genetic diseases (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
CADD	Benign	10
DANN	Benign	0.82
PhyloP100		-0.066
PromoterAI		0.051	Neutral
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: rs1044522; hg19: chr11-66335832; COSMIC: COSV59748841; COSMIC: COSV59748841;