1-150730241-G-C

Variant names:

• chr1-150730241-G-C
• rs1136808
• NM_004079.5:c.*2805C>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_004079.5(CTSS):​c.*2805C>G variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.385 in 151,878 control chromosomes in the GnomAD database, including 11,593 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 0.39 (11593 hom., cov: 31)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: CTSS NM_004079.5 3_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -2.51
• Publications: 9 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=-1.04).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.531 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.*2805C>G		3_prime_UTR	Exon 8 of 8	NP_004070.3
	CTSS	NM_001199739.2		c.*2805C>G		3_prime_UTR	Exon 7 of 7	NP_001186668.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CTSS	ENST00000368985.8	TSL:1 MANE Select	c.*2805C>G		3_prime_UTR	Exon 8 of 8	ENSP00000357981.3
	CTSS	ENST00000472977.7	TSL:5	n.*1025C>G		non_coding_transcript_exon	Exon 9 of 9	ENSP00000475176.2
	CTSS	ENST00000607427.2	TSL:2	n.*1018C>G		non_coding_transcript_exon	Exon 9 of 9	ENSP00000475557.2

Frequencies

GnomAD3 genomes AF: 0.385 AC: 58470 AN: 151758 Hom.: 11583 Cov.: 31

Gnomad AFR AF: 0.308

Gnomad AMI AF: 0.267

Gnomad AMR AF: 0.435

Gnomad ASJ AF: 0.493

Gnomad EAS AF: 0.356

Gnomad SAS AF: 0.549

Gnomad FIN AF: 0.401

Gnomad MID AF: 0.430

Gnomad NFE AF: 0.405

Gnomad OTH AF: 0.393

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 2 Hom.: 0 Cov.: 0 AF XY: 0.00 AC XY: 0 AN XY: 2

African (AFR) AC: 0 AN: 0

American (AMR) AC: 0 AN: 0

Ashkenazi Jewish (ASJ) AC: 0 AN: 0

East Asian (EAS) AC: 0 AN: 0

South Asian (SAS) AC: 0 AN: 0

European-Finnish (FIN) AC: 0 AN: 0

Middle Eastern (MID) AC: 0 AN: 0

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 2

Other (OTH) AC: 0 AN: 0

GnomAD4 genome AF: 0.385 AC: 58498 AN: 151878 Hom.: 11593 Cov.: 31 AF XY: 0.390 AC XY: 28923 AN XY: 74232

African (AFR) AF: 0.308 AC: 12734 AN: 41400

American (AMR) AF: 0.435 AC: 6634 AN: 15264

Ashkenazi Jewish (ASJ) AF: 0.493 AC: 1708 AN: 3468

East Asian (EAS) AF: 0.357 AC: 1846 AN: 5172

South Asian (SAS) AF: 0.549 AC: 2640 AN: 4810

European-Finnish (FIN) AF: 0.401 AC: 4229 AN: 10536

Middle Eastern (MID) AF: 0.422 AC: 124 AN: 294

European-Non Finnish (NFE) AF: 0.405 AC: 27504 AN: 67914

Other (OTH) AF: 0.396 AC: 836 AN: 2110

Alfa AF: 0.393 Hom.: 1588

Bravo AF: 0.377

Asia WGS AF: 0.393 AC: 1367 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-1.0
CADD	Benign	0.52
DANN	Benign	0.21
PhyloP100		-2.5
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: rs1136808; hg19: chr1-150702717; COSMIC: COSV107454269; COSMIC: COSV107454269;