rs11550508

Variant names:

• chr11-66567517-T-C
• rs11550508
• NM_003793.4:c.458A>G

Your query was ambiguous. Multiple possible variants found:

• chr11-66567517-T-C
• chr11-66567517-T-G

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.458A>G​(p.Gln153Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000532 in 1,614,184 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0028 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00030 (4 hom.)
• Consequence: CTSF NM_003793.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -0.110
• Publications: 5 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=0.0038163662).
• BP6: Variant 11-66567517-T-C is Benign according to our data. Variant chr11-66567517-T-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 259170.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 = 0.00276 (420/152296) while in subpopulation AFR AF = 0.0097 (403/41556). AF 95% confidence interval is 0.00892. There are 0 homozygotes in GnomAd4. There are 209 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 4 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.458A>G	p.Gln153Arg	missense	Exon 3 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.458A>G	p.Gln153Arg	missense	Exon 3 of 13	ENSP00000310832.5	Q9UBX1
	CTSF	ENST00000679347.1		c.458A>G	p.Gln153Arg	missense	Exon 3 of 13	ENSP00000503676.1	A0A7I2YQH8
	CTSF	ENST00000677005.1		c.458A>G	p.Gln153Arg	missense	Exon 3 of 13	ENSP00000503238.1	A0A7I2V313

Frequencies

GnomAD3 genomes AF: 0.00275 AC: 419 AN: 152178 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00970

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000654

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00287

GnomAD2 exomes AF: 0.000779 AC: 196 AN: 251492 AF XY: 0.000522

Gnomad AFR exome AF: 0.0109

Gnomad AMR exome AF: 0.000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000439

Gnomad OTH exome AF: 0.000489

GnomAD4 exome AF: 0.000300 AC: 438 AN: 1461888 Hom.: 4 Cov.: 32 AF XY: 0.000228 AC XY: 166 AN XY: 727246

African (AFR) AF: 0.0115 AC: 386 AN: 33480

American (AMR) AF: 0.000358 AC: 16 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53416

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00000629 AC: 7 AN: 1112010

Other (OTH) AF: 0.000480 AC: 29 AN: 60396

GnomAD4 genome AF: 0.00276 AC: 420 AN: 152296 Hom.: 0 Cov.: 32 AF XY: 0.00281 AC XY: 209 AN XY: 74462

African (AFR) AF: 0.00970 AC: 403 AN: 41556

American (AMR) AF: 0.000653 AC: 10 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5172

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

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10618

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

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68028

Other (OTH) AF: 0.00284 AC: 6 AN: 2114

Alfa AF: 0.00155 Hom.: 1

Bravo AF: 0.00307

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00 AC: 0

ESP6500AA AF: 0.00864 AC: 38

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000964 AC: 117

Asia WGS AF: 0.00115 AC: 4 AN: 3478

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.068
BayesDel_addAF	Benign	-0.49	T
BayesDel_noAF	Benign	-0.46
CADD	Benign	2.1
DANN	Benign	0.86
DEOGEN2	Benign	0.065	T
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.092	N
LIST_S2	Benign	0.34	T
MetaRNN	Benign	0.0038	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.90	L
PhyloP100		-0.11
PrimateAI	Benign	0.25	T
PROVEAN	Benign	0.20	N
REVEL	Benign	0.053
Sift	Benign	0.62	T
Sift4G	Benign	0.51	T
Polyphen		0.0040	B
Vest4		0.16
MVP		0.52
MPC		0.26
ClinPred		0.0039	T
GERP RS		-1.3
Varity_R		0.043
gMVP		0.24
Mutation Taster		=96/4	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: rs11550508; hg19: chr11-66334988;