rs12568757

chr1-150757317-G-A

Variant summary

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

The NM_004079.5(CTSS):c.249+541C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.418 in 151,984 control chromosomes in the GnomAD database, including 15,244 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 0.42 (15244 hom., cov: 31)
• Consequence: CTSS NM_004079.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.228

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 (NFE) allele frequency at 95% confidence interval = 0.533 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CTSS	NM_004079.5	c.249+541C>T		intron_variant		ENST00000368985.8
CTSS	NM_001199739.2	c.249+541C>T		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CTSS	ENST00000368985.8	c.249+541C>T		intron_variant		1	NM_004079.5	P1

Frequencies

GnomAD3 genomes AF: 0.418 AC: 63505 AN: 151866 Hom.: 15248 Cov.: 31

Gnomad AFR AF: 0.178

Gnomad AMI AF: 0.604

Gnomad AMR AF: 0.455

Gnomad ASJ AF: 0.375

Gnomad EAS AF: 0.452

Gnomad SAS AF: 0.329

Gnomad FIN AF: 0.557

Gnomad MID AF: 0.418

Gnomad NFE AF: 0.537

Gnomad OTH AF: 0.447

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.418 AC: 63504 AN: 151984 Hom.: 15244 Cov.: 31 AF XY: 0.417 AC XY: 30994 AN XY: 74272

Gnomad4 AFR AF: 0.177

Gnomad4 AMR AF: 0.455

Gnomad4 ASJ AF: 0.375

Gnomad4 EAS AF: 0.451

Gnomad4 SAS AF: 0.331

Gnomad4 FIN AF: 0.557

Gnomad4 NFE AF: 0.537

Gnomad4 OTH AF: 0.443

Alfa AF: 0.503 Hom.: 20128

Bravo AF: 0.404

Asia WGS AF: 0.420 AC: 1462 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	6.7
Dann	Benign	0.40

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: rs12568757; hg19: chr1-150729793;