rs11576175

Variant names:

• chr1-150754918-G-A
• rs11576175
• NM_004079.5:c.399+83C>T

Variant summary

Our verdict is Benign. The variant received -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
• Publications: 25 publications found

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

Our verdict: Benign. The variant received -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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004079.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CTSS	NM_004079.5	MANE Select	c.399+83C>T		intron	N/A	NP_004070.3
	CTSS	NM_001199739.2		c.250-2910C>T		intron	N/A	NP_001186668.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CTSS	ENST00000368985.8	TSL:1 MANE Select	c.399+83C>T		intron	N/A	ENSP00000357981.3
	CTSS	ENST00000857596.1		c.399+83C>T		intron	N/A	ENSP00000527655.1
	CTSS	ENST00000962999.1		c.399+83C>T		intron	N/A	ENSP00000633058.1

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

African (AFR) AF: 0.0114 AC: 323 AN: 28262

American (AMR) AF: 0.0586 AC: 1769 AN: 30184

Ashkenazi Jewish (ASJ) AF: 0.155 AC: 3041 AN: 19646

East Asian (EAS) AF: 0.184 AC: 6962 AN: 37892

South Asian (SAS) AF: 0.114 AC: 7578 AN: 66524

European-Finnish (FIN) AF: 0.0954 AC: 4730 AN: 49596

Middle Eastern (MID) AF: 0.121 AC: 607 AN: 5026

European-Non Finnish (NFE) AF: 0.0865 AC: 83706 AN: 967856

Other (OTH) AF: 0.0903 AC: 4744 AN: 52552

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

African (AFR) AF: 0.0141 AC: 585 AN: 41550

American (AMR) AF: 0.0667 AC: 1020 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.145 AC: 502 AN: 3472

East Asian (EAS) AF: 0.184 AC: 954 AN: 5178

South Asian (SAS) AF: 0.106 AC: 510 AN: 4814

European-Finnish (FIN) AF: 0.0960 AC: 1016 AN: 10586

Middle Eastern (MID) AF: 0.122 AC: 36 AN: 294

European-Non Finnish (NFE) AF: 0.0938 AC: 6381 AN: 68006

Other (OTH) AF: 0.0775 AC: 164 AN: 2116

Alfa AF: 0.0880 Hom.: 1910

Bravo AF: 0.0716

Asia WGS AF: 0.143 AC: 495 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.70
CADD	Benign	4.7
DANN	Benign	0.77
PhyloP100		0.37
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: rs11576175; hg19: chr1-150727394; COSMIC: COSV64566434; COSMIC: COSV64566434;