rs12568757

Variant names:

• chr1-150757317-G-A
• rs12568757
• NM_004079.5:c.249+541C>T

Variant summary

Our verdict is Benign. The variant received -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
• Publications: 31 publications found

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

Our verdict: Benign. The variant received -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 rank	MANE	Protein	UniProt
CTSS	NM_004079.5	c.249+541C>T		intron_variant	Intron 3 of 7	ENST00000368985.8	NP_004070.3
CTSS	NM_001199739.2	c.249+541C>T		intron_variant	Intron 3 of 6		NP_001186668.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CTSS	ENST00000368985.8	c.249+541C>T		intron_variant	Intron 3 of 7	1	NM_004079.5	ENSP00000357981.3

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

African (AFR) AF: 0.177 AC: 7355 AN: 41466

American (AMR) AF: 0.455 AC: 6951 AN: 15268

Ashkenazi Jewish (ASJ) AF: 0.375 AC: 1301 AN: 3466

East Asian (EAS) AF: 0.451 AC: 2329 AN: 5162

South Asian (SAS) AF: 0.331 AC: 1596 AN: 4820

European-Finnish (FIN) AF: 0.557 AC: 5860 AN: 10528

Middle Eastern (MID) AF: 0.422 AC: 124 AN: 294

European-Non Finnish (NFE) AF: 0.537 AC: 36502 AN: 67956

Other (OTH) AF: 0.443 AC: 936 AN: 2114

Alfa AF: 0.491 Hom.: 25314

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
PhyloP100		0.23
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs12568757; hg19: chr1-150729793;