rs12089989

Variant names:

• chr1-150743306-G-A
• rs12089989
• NM_004079.5:c.896+4471C>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.896+4471C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.44 in 151,034 control chromosomes in the GnomAD database, including 14,861 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 0.44 (14861 hom., cov: 29)
• Consequence: CTSS NM_004079.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.911
• Publications: 16 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 (SAS) allele frequency at 95% confidence interval = 0.556 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CTSS	NM_004079.5	c.896+4471C>T		intron_variant	Intron 7 of 7	ENST00000368985.8	NP_004070.3
CTSS	NM_001199739.2	c.746+4471C>T		intron_variant	Intron 6 of 6		NP_001186668.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CTSS	ENST00000368985.8	c.896+4471C>T		intron_variant	Intron 7 of 7	1	NM_004079.5	ENSP00000357981.3

Frequencies

GnomAD3 genomes AF: 0.440 AC: 66391 AN: 150924 Hom.: 14851 Cov.: 29

Gnomad AFR AF: 0.494

Gnomad AMI AF: 0.265

Gnomad AMR AF: 0.456

Gnomad ASJ AF: 0.492

Gnomad EAS AF: 0.365

Gnomad SAS AF: 0.575

Gnomad FIN AF: 0.402

Gnomad MID AF: 0.449

Gnomad NFE AF: 0.406

Gnomad OTH AF: 0.430

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

GnomAD4 genome AF: 0.440 AC: 66429 AN: 151034 Hom.: 14861 Cov.: 29 AF XY: 0.443 AC XY: 32639 AN XY: 73720

African (AFR) AF: 0.493 AC: 20296 AN: 41138

American (AMR) AF: 0.456 AC: 6858 AN: 15050

Ashkenazi Jewish (ASJ) AF: 0.492 AC: 1708 AN: 3470

East Asian (EAS) AF: 0.365 AC: 1882 AN: 5154

South Asian (SAS) AF: 0.574 AC: 2748 AN: 4786

European-Finnish (FIN) AF: 0.402 AC: 4146 AN: 10324

Middle Eastern (MID) AF: 0.438 AC: 128 AN: 292

European-Non Finnish (NFE) AF: 0.406 AC: 27519 AN: 67830

Other (OTH) AF: 0.433 AC: 904 AN: 2086

Alfa AF: 0.433 Hom.: 10960

Bravo AF: 0.438

Asia WGS AF: 0.420 AC: 1460 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	2.7
DANN	Benign	0.55
PhyloP100		0.91
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: rs12089989; hg19: chr1-150715782;