rs1136774

Positions:

• chr1-150765721-C-T

Variant summary

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

The NM_004079.5(CTSS):​c.-25G>A variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.413 in 152,086 control chromosomes in the GnomAD database, including 15,033 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 0.41 (15033 hom., cov: 31)
  • Failed GnomAD Quality Control
• Consequence: CTSS NM_004079.5 5_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0200

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=-0.8).
• BA1: GnomAd4 highest subpopulation (NFE) 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.-25G>A		5_prime_UTR_variant	1/8	ENST00000368985.8
CTSS	NM_001199739.2	c.-25G>A		5_prime_UTR_variant	1/7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CTSS	ENST00000368985.8	c.-25G>A		5_prime_UTR_variant	1/8	1	NM_004079.5	P1

Frequencies

GnomAD3 genomes AF: 0.413 AC: 62780 AN: 151968 Hom.: 15034 Cov.: 31

Gnomad AFR AF: 0.167

Gnomad AMI AF: 0.602

Gnomad AMR AF: 0.452

Gnomad ASJ AF: 0.371

Gnomad EAS AF: 0.416

Gnomad SAS AF: 0.327

Gnomad FIN AF: 0.557

Gnomad MID AF: 0.408

Gnomad NFE AF: 0.536

Gnomad OTH AF: 0.440

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: 0.413 AC: 62782 AN: 152086 Hom.: 15033 Cov.: 31 AF XY: 0.412 AC XY: 30632 AN XY: 74358

Gnomad4 AFR AF: 0.167

Gnomad4 AMR AF: 0.452

Gnomad4 ASJ AF: 0.371

Gnomad4 EAS AF: 0.415

Gnomad4 SAS AF: 0.329

Gnomad4 FIN AF: 0.557

Gnomad4 NFE AF: 0.536

Gnomad4 OTH AF: 0.436

Alfa AF: 0.485 Hom.: 3988

Bravo AF: 0.399

Asia WGS AF: 0.390 AC: 1360 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
CADD	Benign	5.3
DANN	Benign	0.61

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs1136774; hg19: chr1-150738197;