rs4630309

Variant names:

• chr11-66565601-C-A
• rs4630309
• NM_003793.4:c.1045+70G>T

Your query was ambiguous. Multiple possible variants found:

• chr11-66565601-C-A
• chr11-66565601-C-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.1045+70G>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.242 in 1,590,354 control chromosomes in the GnomAD database, including 48,317 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.23 (4359 hom., cov: 32)
  • Exomes 𝑓: 0.24 (43958 hom.)
• Consequence: CTSF NM_003793.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 1.33
• Publications: 20 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=-0.84).
• BP6: Variant 11-66565601-C-A is Benign according to our data. Variant chr11-66565601-C-A is described in ClinVar as Benign. ClinVar VariationId is 1222574.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.274 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CTSF	NM_003793.4	c.1045+70G>T		intron_variant	Intron 8 of 12	ENST00000310325.10	NP_003784.2
CTSF	XM_011545328.3	c.865+70G>T		intron_variant	Intron 8 of 12		XP_011543630.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CTSF	ENST00000310325.10	c.1045+70G>T		intron_variant	Intron 8 of 12	1	NM_003793.4	ENSP00000310832.5

Frequencies

GnomAD3 genomes AF: 0.231 AC: 35192 AN: 152036 Hom.: 4348 Cov.: 32

Gnomad AFR AF: 0.191

Gnomad AMI AF: 0.234

Gnomad AMR AF: 0.176

Gnomad ASJ AF: 0.151

Gnomad EAS AF: 0.286

Gnomad SAS AF: 0.225

Gnomad FIN AF: 0.387

Gnomad MID AF: 0.123

Gnomad NFE AF: 0.247

Gnomad OTH AF: 0.197

GnomAD4 exome AF: 0.243 AC: 349852 AN: 1438200 Hom.: 43958 AF XY: 0.243 AC XY: 174268 AN XY: 715688

African (AFR) AF: 0.186 AC: 6137 AN: 32932

American (AMR) AF: 0.145 AC: 6458 AN: 44610

Ashkenazi Jewish (ASJ) AF: 0.167 AC: 4347 AN: 25994

East Asian (EAS) AF: 0.268 AC: 10584 AN: 39486

South Asian (SAS) AF: 0.236 AC: 20173 AN: 85558

European-Finnish (FIN) AF: 0.373 AC: 19444 AN: 52132

Middle Eastern (MID) AF: 0.137 AC: 602 AN: 4406

European-Non Finnish (NFE) AF: 0.245 AC: 268445 AN: 1093624

Other (OTH) AF: 0.230 AC: 13662 AN: 59458

GnomAD4 genome AF: 0.232 AC: 35234 AN: 152154 Hom.: 4359 Cov.: 32 AF XY: 0.237 AC XY: 17607 AN XY: 74396

African (AFR) AF: 0.191 AC: 7935 AN: 41532

American (AMR) AF: 0.176 AC: 2698 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.151 AC: 523 AN: 3470

East Asian (EAS) AF: 0.286 AC: 1478 AN: 5170

South Asian (SAS) AF: 0.225 AC: 1087 AN: 4826

European-Finnish (FIN) AF: 0.387 AC: 4089 AN: 10576

Middle Eastern (MID) AF: 0.126 AC: 37 AN: 294

European-Non Finnish (NFE) AF: 0.247 AC: 16766 AN: 67970

Other (OTH) AF: 0.193 AC: 408 AN: 2112

Alfa AF: 0.219 Hom.: 5079

Bravo AF: 0.212

Asia WGS AF: 0.261 AC: 908 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

- -

Jul 15, 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	-0.84
CADD	Benign	6.3
DANN	Benign	0.29
PhyloP100		1.3
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: rs4630309; hg19: chr11-66333072; COSMIC: COSV59748889; COSMIC: COSV59748889;