rs4537557

chr1-150761960-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.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

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=-0.91).
• 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/exons	MANE	UniProt
CTSS	NM_004079.5	c.126+2678T>C		intron_variant		ENST00000368985.8
CTSS	NM_001199739.2	c.126+2678T>C		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CTSS	ENST00000368985.8	c.126+2678T>C		intron_variant		1	NM_004079.5	P1

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

Gnomad4 AFR AF: 0.274

Gnomad4 AMR AF: 0.408

Gnomad4 ASJ AF: 0.437

Gnomad4 EAS AF: 0.390

Gnomad4 SAS AF: 0.532

Gnomad4 FIN AF: 0.344

Gnomad4 NFE AF: 0.356

Gnomad4 OTH AF: 0.356

Alfa AF: 0.347 Hom.: 1513

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

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: rs4537557; hg19: chr1-150734436;