rs1127894

Variant names:

• chr11-66568077-A-C
• rs1127894
• NM_003793.4:c.219T>G

Your query was ambiguous. Multiple possible variants found:

• chr11-66568077-A-C
• chr11-66568077-A-G
• chr11-66568077-A-T

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 2P and 5B. PM2 BP4_Strong BP7

The NM_003793.4(CTSF):​c.219T>G​(p.Gly73Gly) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000559 in 1,432,304 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. G73G) has been classified as Benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000056 (0 hom.)
• Consequence: CTSF NM_003793.4 synonymous
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.00700
• Publications: 19 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: Likely_benign. The variant received -3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.87).
• BP7: Synonymous conserved (PhyloP=0.007 with no splicing effect.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CTSF	NM_003793.4	c.219T>G	p.Gly73Gly	synonymous_variant	Exon 2 of 13	ENST00000310325.10	NP_003784.2
CTSF	XM_011545328.3	c.39T>G	p.Gly13Gly	synonymous_variant	Exon 2 of 13		XP_011543630.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CTSF	ENST00000310325.10	c.219T>G	p.Gly73Gly	synonymous_variant	Exon 2 of 13	1	NM_003793.4	ENSP00000310832.5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.000110 AC: 21 AN: 191340 AF XY: 0.000124

Gnomad AFR exome AF: 0.000200

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000145

Gnomad FIN exome AF: 0.000243

Gnomad NFE exome AF: 0.000144

Gnomad OTH exome AF: 0.000206

GnomAD4 exome AF: 0.00000559 AC: 8 AN: 1432304 Hom.: 0 Cov.: 47 AF XY: 0.00000703 AC XY: 5 AN XY: 711028

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.0000317 AC: 1 AN: 31514

American (AMR) AF: 0.00 AC: 0 AN: 39820

Ashkenazi Jewish (ASJ) AF: 0.0000396 AC: 1 AN: 25258

East Asian (EAS) AF: 0.0000530 AC: 2 AN: 37740

South Asian (SAS) AF: 0.00 AC: 0 AN: 83280

European-Finnish (FIN) AF: 0.0000199 AC: 1 AN: 50294

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4968

European-Non Finnish (NFE) AF: 0.00000273 AC: 3 AN: 1100350

Other (OTH) AF: 0.00 AC: 0 AN: 59080

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	8.2
DANN	Benign	0.58
PhyloP100		0.0070
PromoterAI		-0.0062	Neutral

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: rs1127894; hg19: chr11-66335548; COSMIC: COSV59750020;