rs1415148

chr1-150733279-G-Achr1-150733279-G-Cchr1-150733279-G-T

Variant summary

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

The NM_004079.5(CTSS):c.897-134C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.406 in 604,912 control chromosomes in the GnomAD database, including 51,143 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 0.39 (11592 hom., cov: 32)
  • Exomes 𝑓: 0.41 (39551 hom.)
• Consequence: CTSS NM_004079.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.406

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=-0.97).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.532 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CTSS	NM_004079.5	c.897-134C>T		intron_variant		ENST00000368985.8
CTSS	NM_001199739.2	c.747-134C>T		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CTSS	ENST00000368985.8	c.897-134C>T		intron_variant		1	NM_004079.5	P1

Frequencies

GnomAD3 genomes AF: 0.386 AC: 58541 AN: 151844 Hom.: 11582 Cov.: 32

Gnomad AFR AF: 0.309

Gnomad AMI AF: 0.266

Gnomad AMR AF: 0.435

Gnomad ASJ AF: 0.492

Gnomad EAS AF: 0.357

Gnomad SAS AF: 0.550

Gnomad FIN AF: 0.402

Gnomad MID AF: 0.429

Gnomad NFE AF: 0.405

Gnomad OTH AF: 0.394

GnomAD4 exome AF: 0.412 AC: 186840 AN: 452950 Hom.: 39551 AF XY: 0.419 AC XY: 100389 AN XY: 239606

Gnomad4 AFR exome AF: 0.313

Gnomad4 AMR exome AF: 0.421

Gnomad4 ASJ exome AF: 0.489

Gnomad4 EAS exome AF: 0.369

Gnomad4 SAS exome AF: 0.536

Gnomad4 FIN exome AF: 0.402

Gnomad4 NFE exome AF: 0.399

Gnomad4 OTH exome AF: 0.411

GnomAD4 genome AF: 0.385 AC: 58569 AN: 151962 Hom.: 11592 Cov.: 32 AF XY: 0.390 AC XY: 28965 AN XY: 74294

Gnomad4 AFR AF: 0.309

Gnomad4 AMR AF: 0.435

Gnomad4 ASJ AF: 0.492

Gnomad4 EAS AF: 0.357

Gnomad4 SAS AF: 0.549

Gnomad4 FIN AF: 0.402

Gnomad4 NFE AF: 0.405

Gnomad4 OTH AF: 0.398

Alfa AF: 0.392 Hom.: 1908

Bravo AF: 0.377

Asia WGS AF: 0.391 AC: 1360 AN: 3476

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.97
Cadd	Benign	5.5
Dann	Benign	0.37

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: rs1415148; hg19: chr1-150705755;