rs11587444

Positions:

• chr1-150750368-A-G

Variant summary

Our verdict is Benign. Variant got -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

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=-0.88).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.525 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CTSS	NM_004079.5	c.628-197T>C		intron_variant		ENST00000368985.8
CTSS	NM_001199739.2	c.478-197T>C		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CTSS	ENST00000368985.8	c.628-197T>C		intron_variant		1	NM_004079.5	P1

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

Gnomad4 AFR AF: 0.305

Gnomad4 AMR AF: 0.425

Gnomad4 ASJ AF: 0.450

Gnomad4 EAS AF: 0.363

Gnomad4 SAS AF: 0.542

Gnomad4 FIN AF: 0.398

Gnomad4 NFE AF: 0.395

Gnomad4 OTH AF: 0.385

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 v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	4.3
DANN	Benign	0.62

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: rs11587444; hg19: chr1-150722844;