chr11-66563714-TACC-T

Variant names:

• chr11-66563714-TACC-T
• rs201073320
• NM_003793.4:c.*216_*218delGGT

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP6_Moderate BS1 BS2

The NM_003793.4(CTSF):​c.*216_*218delGGT variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0176 in 616,354 control chromosomes in the GnomAD database, including 113 homozygotes. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.015 (20 hom., cov: 32)
  • Exomes 𝑓: 0.018 (93 hom.)
• Consequence: CTSF NM_003793.4 3_prime_UTR
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 1.90
• Publications: 1 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: Unknown, AR Classification: DEFINITIVE, STRONG, SUPPORTIVE, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Genomics England PanelApp, Ambry Genetics, Orphanet

ACMG classification

Our verdict: Benign. The variant received -10 ACMG points.

• BP6: Variant 11-66563714-TACC-T is Benign according to our data. Variant chr11-66563714-TACC-T is described in ClinVar as Likely_benign. ClinVar VariationId is 1185770.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0151 (2306/152306) while in subpopulation NFE AF = 0.0238 (1617/68020). AF 95% confidence interval is 0.0228. There are 20 homozygotes in GnomAd4. There are 1078 alleles in the male GnomAd4 subpopulation. Median coverage is 32. 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.*216_*218delGGT		3_prime_UTR	Exon 13 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.*216_*218delGGT		3_prime_UTR	Exon 13 of 13	ENSP00000310832.5	Q9UBX1
	CTSF	ENST00000679347.1		c.*248_*250delGGT		3_prime_UTR	Exon 13 of 13	ENSP00000503676.1	A0A7I2YQH8
	CTSF	ENST00000677005.1		c.*248_*250delGGT		3_prime_UTR	Exon 13 of 13	ENSP00000503238.1	A0A7I2V313

Frequencies

GnomAD3 genomes AF: 0.0152 AC: 2310 AN: 152188 Hom.: 20 Cov.: 32

Gnomad AFR AF: 0.00506

Gnomad AMI AF: 0.0121

Gnomad AMR AF: 0.0168

Gnomad ASJ AF: 0.00980

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.00166

Gnomad FIN AF: 0.0112

Gnomad MID AF: 0.0190

Gnomad NFE AF: 0.0238

Gnomad OTH AF: 0.0211

GnomAD4 exome AF: 0.0185 AC: 8566 AN: 464048 Hom.: 93 AF XY: 0.0172 AC XY: 4168 AN XY: 242490

African (AFR) AF: 0.00410 AC: 52 AN: 12686

American (AMR) AF: 0.0179 AC: 335 AN: 18762

Ashkenazi Jewish (ASJ) AF: 0.0101 AC: 139 AN: 13764

East Asian (EAS) AF: 0.00 AC: 0 AN: 31106

South Asian (SAS) AF: 0.00139 AC: 63 AN: 45310

European-Finnish (FIN) AF: 0.00990 AC: 292 AN: 29508

Middle Eastern (MID) AF: 0.0207 AC: 41 AN: 1984

European-Non Finnish (NFE) AF: 0.0250 AC: 7110 AN: 284370

Other (OTH) AF: 0.0201 AC: 534 AN: 26558

GnomAD4 genome AF: 0.0151 AC: 2306 AN: 152306 Hom.: 20 Cov.: 32 AF XY: 0.0145 AC XY: 1078 AN XY: 74472

African (AFR) AF: 0.00505 AC: 210 AN: 41584

American (AMR) AF: 0.0167 AC: 256 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.00980 AC: 34 AN: 3470

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5188

South Asian (SAS) AF: 0.00166 AC: 8 AN: 4818

European-Finnish (FIN) AF: 0.0112 AC: 119 AN: 10614

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

European-Non Finnish (NFE) AF: 0.0238 AC: 1617 AN: 68020

Other (OTH) AF: 0.0208 AC: 44 AN: 2112

Alfa AF: 0.0186 Hom.: 4

Bravo AF: 0.0161

Asia WGS AF: 0.00318 AC: 11 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Likely benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		1.9
Mutation Taster		=98/2	polymorphism

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: rs201073320; hg19: chr11-66331185;