rs4537557

Variant names:

• chr1-150761960-A-G
• rs4537557
• NM_004079.5:c.126+2678T>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.126+2678T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.346 in 152,058 control chromosomes in the GnomAD database, including 9,443 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 (9443 hom., cov: 32)
• Consequence: CTSS NM_004079.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.602
• Publications: 10 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=-0.91).
• 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 rank	MANE	Protein	UniProt
CTSS	NM_004079.5	c.126+2678T>C		intron_variant	Intron 2 of 7	ENST00000368985.8	NP_004070.3
CTSS	NM_001199739.2	c.126+2678T>C		intron_variant	Intron 2 of 6		NP_001186668.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CTSS	ENST00000368985.8	c.126+2678T>C		intron_variant	Intron 2 of 7	1	NM_004079.5	ENSP00000357981.3

Frequencies

GnomAD3 genomes AF: 0.346 AC: 52621 AN: 151940 Hom.: 9436 Cov.: 32

Gnomad AFR AF: 0.274

Gnomad AMI AF: 0.266

Gnomad AMR AF: 0.408

Gnomad ASJ AF: 0.437

Gnomad EAS AF: 0.389

Gnomad SAS AF: 0.533

Gnomad FIN AF: 0.344

Gnomad MID AF: 0.415

Gnomad NFE AF: 0.356

Gnomad OTH AF: 0.352

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

GnomAD4 genome AF: 0.346 AC: 52641 AN: 152058 Hom.: 9443 Cov.: 32 AF XY: 0.352 AC XY: 26154 AN XY: 74340

African (AFR) AF: 0.274 AC: 11363 AN: 41472

American (AMR) AF: 0.408 AC: 6227 AN: 15268

Ashkenazi Jewish (ASJ) AF: 0.437 AC: 1515 AN: 3468

East Asian (EAS) AF: 0.390 AC: 2019 AN: 5182

South Asian (SAS) AF: 0.532 AC: 2571 AN: 4830

European-Finnish (FIN) AF: 0.344 AC: 3632 AN: 10550

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

European-Non Finnish (NFE) AF: 0.356 AC: 24202 AN: 67974

Other (OTH) AF: 0.356 AC: 751 AN: 2110

Alfa AF: 0.345 Hom.: 1541

Bravo AF: 0.341

Asia WGS AF: 0.410 AC: 1423 AN: 3476

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	5.1
DANN	Benign	0.61
PhyloP100		0.60
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: rs4537557; hg19: chr1-150734436;