rs11576175

Positions:

• chr1-150754918-G-A

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_004079.5(CTSS):​c.399+83C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0885 in 1,409,766 control chromosomes in the GnomAD database, including 6,345 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.074 (590 hom., cov: 32)
  • Exomes 𝑓: 0.090 (5755 hom.)
• Consequence: CTSS NM_004079.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.373

Genes affected

CTSS (HGNC:2545): (cathepsin S) The preproprotein encoded by this gene, a member of the peptidase C1 family, is a lysosomal cysteine proteinase that participates in the degradation of antigenic proteins to peptides for presentation on MHC class II molecules. The mature protein cleaves the invariant chain of MHC class II molecules in endolysosomal compartments and enables the formation of antigen-MHC class II complexes and the proper display of extracellular antigenic peptides by MHC-II. The mature protein also functions as an elastase over a broad pH range. When secreted from cells, this protein can remodel components of the extracellular matrix such as elastin, collagen, and fibronectin. This gene is implicated in the pathology of many inflammatory and autoimmune diseases and, given its elastase activity, plays a significant role in some pulmonary diseases. Alternatively spliced transcript variants encoding distinct isoforms have been found for this gene. [provided by RefSeq, May 2020]

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.7).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.175 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CTSS	NM_004079.5	c.399+83C>T		intron_variant		ENST00000368985.8
CTSS	NM_001199739.2	c.250-2910C>T		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CTSS	ENST00000368985.8	c.399+83C>T		intron_variant		1	NM_004079.5	P1

Frequencies

GnomAD3 genomes AF: 0.0741 AC: 11275 AN: 152110 Hom.: 587 Cov.: 32

Gnomad AFR AF: 0.0141

Gnomad AMI AF: 0.130

Gnomad AMR AF: 0.0664

Gnomad ASJ AF: 0.145

Gnomad EAS AF: 0.183

Gnomad SAS AF: 0.106

Gnomad FIN AF: 0.0960

Gnomad MID AF: 0.117

Gnomad NFE AF: 0.0938

Gnomad OTH AF: 0.0759

GnomAD4 exome AF: 0.0902 AC: 113460 AN: 1257538 Hom.: 5755 AF XY: 0.0916 AC XY: 56860 AN XY: 620860

Gnomad4 AFR exome AF: 0.0114

Gnomad4 AMR exome AF: 0.0586

Gnomad4 ASJ exome AF: 0.155

Gnomad4 EAS exome AF: 0.184

Gnomad4 SAS exome AF: 0.114

Gnomad4 FIN exome AF: 0.0954

Gnomad4 NFE exome AF: 0.0865

Gnomad4 OTH exome AF: 0.0903

GnomAD4 genome AF: 0.0741 AC: 11287 AN: 152228 Hom.: 590 Cov.: 32 AF XY: 0.0746 AC XY: 5551 AN XY: 74420

Gnomad4 AFR AF: 0.0141

Gnomad4 AMR AF: 0.0667

Gnomad4 ASJ AF: 0.145

Gnomad4 EAS AF: 0.184

Gnomad4 SAS AF: 0.106

Gnomad4 FIN AF: 0.0960

Gnomad4 NFE AF: 0.0938

Gnomad4 OTH AF: 0.0775

Alfa AF: 0.0944 Hom.: 1259

Bravo AF: 0.0716

Asia WGS AF: 0.143 AC: 495 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.70
CADD	Benign	4.7
DANN	Benign	0.77

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

Publications

LitVar

Other links and lift over

dbSNP: rs11576175; hg19: chr1-150727394; COSMIC: COSV64566434; COSMIC: COSV64566434;