rs11587444

Variant names:

• chr1-150750368-A-G
• rs11587444
• NM_004079.5:c.628-197T>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_004079.5(CTSS):​c.628-197T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.378 in 152,014 control chromosomes in the GnomAD database, including 11,104 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 0.38 (11104 hom., cov: 31)
• Consequence: CTSS NM_004079.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.189
• Publications: 15 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=-0.88).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.525 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CTSS	NM_004079.5	MANE Select	c.628-197T>C		intron	N/A	NP_004070.3
	CTSS	NM_001199739.2		c.478-197T>C		intron	N/A	NP_001186668.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CTSS	ENST00000368985.8	TSL:1 MANE Select	c.628-197T>C		intron	N/A	ENSP00000357981.3
	CTSS	ENST00000857596.1		c.628-197T>C		intron	N/A	ENSP00000527655.1
	CTSS	ENST00000962999.1		c.628-197T>C		intron	N/A	ENSP00000633058.1

Frequencies

GnomAD3 genomes AF: 0.378 AC: 57369 AN: 151896 Hom.: 11095 Cov.: 31

Gnomad AFR AF: 0.305

Gnomad AMI AF: 0.269

Gnomad AMR AF: 0.425

Gnomad ASJ AF: 0.450

Gnomad EAS AF: 0.362

Gnomad SAS AF: 0.543

Gnomad FIN AF: 0.398

Gnomad MID AF: 0.418

Gnomad NFE AF: 0.395

Gnomad OTH AF: 0.381

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.378 AC: 57396 AN: 152014 Hom.: 11104 Cov.: 31 AF XY: 0.382 AC XY: 28417 AN XY: 74308

African (AFR) AF: 0.305 AC: 12637 AN: 41442

American (AMR) AF: 0.425 AC: 6486 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.450 AC: 1561 AN: 3468

East Asian (EAS) AF: 0.363 AC: 1870 AN: 5158

South Asian (SAS) AF: 0.542 AC: 2613 AN: 4822

European-Finnish (FIN) AF: 0.398 AC: 4206 AN: 10566

Middle Eastern (MID) AF: 0.408 AC: 120 AN: 294

European-Non Finnish (NFE) AF: 0.395 AC: 26848 AN: 67976

Other (OTH) AF: 0.385 AC: 811 AN: 2106

Alfa AF: 0.383 Hom.: 1822

Bravo AF: 0.369

Asia WGS AF: 0.393 AC: 1365 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	4.3
DANN	Benign	0.62
PhyloP100		0.19
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: rs11587444; hg19: chr1-150722844;