rs7540874

Positions:

• chr1-150730187-A-C
• chr1-150730187-A-T

Variant summary

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

The ENST00000680288.1(CTSS):​c.*2859T>G variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.385 in 151,918 control chromosomes in the GnomAD database, including 11,574 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 (11574 hom., cov: 31)
  • Failed GnomAD Quality Control
• Consequence: CTSS ENST00000680288.1 3_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.575

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=-0.93).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.531 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CTSS	NM_004079.5			downstream_gene_variant		ENST00000368985.8
CTSS	NM_001199739.2			downstream_gene_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CTSS	ENST00000368985.8			downstream_gene_variant		1	NM_004079.5	P1

Frequencies

GnomAD3 genomes AF: 0.385 AC: 58415 AN: 151800 Hom.: 11564 Cov.: 31

Gnomad AFR AF: 0.307

Gnomad AMI AF: 0.268

Gnomad AMR AF: 0.435

Gnomad ASJ AF: 0.492

Gnomad EAS AF: 0.355

Gnomad SAS AF: 0.549

Gnomad FIN AF: 0.401

Gnomad MID AF: 0.430

Gnomad NFE AF: 0.405

Gnomad OTH AF: 0.393

GnomAD4 exome Data not reliable, filtered out with message: AC0 AC: 0 AN: 0 Hom.: 0 Cov.: 0 AC XY: 0 AN XY: 0

GnomAD4 genome AF: 0.385 AC: 58443 AN: 151918 Hom.: 11574 Cov.: 31 AF XY: 0.389 AC XY: 28883 AN XY: 74228

Gnomad4 AFR AF: 0.307

Gnomad4 AMR AF: 0.434

Gnomad4 ASJ AF: 0.492

Gnomad4 EAS AF: 0.356

Gnomad4 SAS AF: 0.548

Gnomad4 FIN AF: 0.401

Gnomad4 NFE AF: 0.405

Gnomad4 OTH AF: 0.397

Alfa AF: 0.337 Hom.: 1954

Bravo AF: 0.377

Asia WGS AF: 0.393 AC: 1367 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.93
CADD	Benign	3.6
DANN	Benign	0.44

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs7540874; hg19: chr1-150702663;