chr1-150743306-G-A

Position:

• chr1-150743306-G-A

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The ENST00000368985.8(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 ENST00000368985.8 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.911

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=-0.88).
• 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/exons	MANE	Protein	UniProt
CTSS	NM_004079.5	c.896+4471C>T		intron_variant		ENST00000368985.8	NP_004070.3
CTSS	NM_001199739.2	c.746+4471C>T		intron_variant			NP_001186668.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CTSS	ENST00000368985.8	c.896+4471C>T		intron_variant		1	NM_004079.5	ENSP00000357981	P1

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

Gnomad4 AFR AF: 0.493

Gnomad4 AMR AF: 0.456

Gnomad4 ASJ AF: 0.492

Gnomad4 EAS AF: 0.365

Gnomad4 SAS AF: 0.574

Gnomad4 FIN AF: 0.402

Gnomad4 NFE AF: 0.406

Gnomad4 OTH AF: 0.433

Alfa AF: 0.424 Hom.: 6471

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

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: rs12089989; hg19: chr1-150715782;