1-150757803-A-G

Position:

• chr1-150757803-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.249+55T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.365 in 1,571,476 control chromosomes in the GnomAD database, including 106,920 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 0.35 (9434 hom., cov: 30)
  • Exomes 𝑓: 0.37 (97486 hom.)
• Consequence: CTSS NM_004079.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.33

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=-0.76).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.515 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CTSS	NM_004079.5	c.249+55T>C		intron_variant		ENST00000368985.8	NP_004070.3
CTSS	NM_001199739.2	c.249+55T>C		intron_variant			NP_001186668.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CTSS	ENST00000368985.8	c.249+55T>C		intron_variant		1	NM_004079.5	ENSP00000357981	P1

Frequencies

GnomAD3 genomes AF: 0.346 AC: 52592 AN: 151800 Hom.: 9427 Cov.: 30

Gnomad AFR AF: 0.274

Gnomad AMI AF: 0.268

Gnomad AMR AF: 0.408

Gnomad ASJ AF: 0.437

Gnomad EAS AF: 0.391

Gnomad SAS AF: 0.533

Gnomad FIN AF: 0.345

Gnomad MID AF: 0.415

Gnomad NFE AF: 0.356

Gnomad OTH AF: 0.350

GnomAD4 exome AF: 0.367 AC: 520907 AN: 1419558 Hom.: 97486 AF XY: 0.372 AC XY: 261523 AN XY: 702924

Gnomad4 AFR exome AF: 0.280

Gnomad4 AMR exome AF: 0.400

Gnomad4 ASJ exome AF: 0.429

Gnomad4 EAS exome AF: 0.380

Gnomad4 SAS exome AF: 0.522

Gnomad4 FIN exome AF: 0.351

Gnomad4 NFE exome AF: 0.354

Gnomad4 OTH exome AF: 0.380

GnomAD4 genome AF: 0.346 AC: 52612 AN: 151918 Hom.: 9434 Cov.: 30 AF XY: 0.352 AC XY: 26123 AN XY: 74232

Gnomad4 AFR AF: 0.274

Gnomad4 AMR AF: 0.408

Gnomad4 ASJ AF: 0.437

Gnomad4 EAS AF: 0.391

Gnomad4 SAS AF: 0.532

Gnomad4 FIN AF: 0.345

Gnomad4 NFE AF: 0.356

Gnomad4 OTH AF: 0.354

Alfa AF: 0.347 Hom.: 1521

Bravo AF: 0.341

Asia WGS AF: 0.410 AC: 1425 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.76
CADD	Benign	6.9
DANN	Benign	0.85

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: rs2275235; hg19: chr1-150730279; COSMIC: COSV64566038;