1-150757803-A-G

Variant names:

• chr1-150757803-A-G
• rs2275235
• NM_004079.5:c.249+55T>C

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+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
• Publications: 26 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=-0.76).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.515 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004079.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CTSS	NM_004079.5	MANE Select	c.249+55T>C		intron	N/A	NP_004070.3
	CTSS	NM_001199739.2		c.249+55T>C		intron	N/A	NP_001186668.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CTSS	ENST00000368985.8	TSL:1 MANE Select	c.249+55T>C		intron	N/A	ENSP00000357981.3
	CTSS	ENST00000681863.1		n.452T>C		non_coding_transcript_exon	Exon 3 of 3
	CTSS	ENST00000679512.1		c.249+55T>C		intron	N/A	ENSP00000505113.1

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

African (AFR) AF: 0.280 AC: 9095 AN: 32482

American (AMR) AF: 0.400 AC: 16663 AN: 41706

Ashkenazi Jewish (ASJ) AF: 0.429 AC: 10756 AN: 25084

East Asian (EAS) AF: 0.380 AC: 14822 AN: 38962

South Asian (SAS) AF: 0.522 AC: 43747 AN: 83872

European-Finnish (FIN) AF: 0.351 AC: 18430 AN: 52568

Middle Eastern (MID) AF: 0.421 AC: 2369 AN: 5626

European-Non Finnish (NFE) AF: 0.354 AC: 382873 AN: 1080940

Other (OTH) AF: 0.380 AC: 22152 AN: 58318

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

African (AFR) AF: 0.274 AC: 11364 AN: 41436

American (AMR) AF: 0.408 AC: 6229 AN: 15264

Ashkenazi Jewish (ASJ) AF: 0.437 AC: 1513 AN: 3466

East Asian (EAS) AF: 0.391 AC: 2022 AN: 5168

South Asian (SAS) AF: 0.532 AC: 2562 AN: 4812

European-Finnish (FIN) AF: 0.345 AC: 3631 AN: 10536

Middle Eastern (MID) AF: 0.405 AC: 119 AN: 294

European-Non Finnish (NFE) AF: 0.356 AC: 24183 AN: 67930

Other (OTH) AF: 0.354 AC: 747 AN: 2108

Alfa AF: 0.345 Hom.: 1549

Bravo AF: 0.341

Asia WGS AF: 0.410 AC: 1425 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.76
CADD	Benign	6.9
DANN	Benign	0.85
PhyloP100		2.3
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: rs2275235; hg19: chr1-150730279; COSMIC: COSV64566038;