rs1136774

Variant names:

• chr1-150765721-C-T
• rs1136774
• NM_004079.5:c.-25G>A

Variant summary

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

The NM_004079.5(CTSS):​c.-25G>A variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.413 in 152,086 control chromosomes in the GnomAD database, including 15,033 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 0.41 (15033 hom., cov: 31)
  • Failed GnomAD Quality Control
• Consequence: CTSS NM_004079.5 5_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0200
• Publications: 22 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=-0.8).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.532 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CTSS	NM_004079.5	MANE Select	c.-25G>A		5_prime_UTR	Exon 1 of 8	NP_004070.3
	CTSS	NM_001199739.2		c.-25G>A		5_prime_UTR	Exon 1 of 7	NP_001186668.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CTSS	ENST00000368985.8	TSL:1 MANE Select	c.-25G>A		5_prime_UTR	Exon 1 of 8	ENSP00000357981.3
	CTSS	ENST00000962999.1		c.-25G>A		5_prime_UTR	Exon 1 of 8	ENSP00000633058.1
	CTSS	ENST00000857595.1		c.-25G>A		5_prime_UTR	Exon 1 of 8	ENSP00000527654.1

Frequencies

GnomAD3 genomes AF: 0.413 AC: 62780 AN: 151968 Hom.: 15034 Cov.: 31

Gnomad AFR AF: 0.167

Gnomad AMI AF: 0.602

Gnomad AMR AF: 0.452

Gnomad ASJ AF: 0.371

Gnomad EAS AF: 0.416

Gnomad SAS AF: 0.327

Gnomad FIN AF: 0.557

Gnomad MID AF: 0.408

Gnomad NFE AF: 0.536

Gnomad OTH AF: 0.440

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

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) AC: 0 AN: 0

Other (OTH) AC: 0 AN: 0

GnomAD4 genome AF: 0.413 AC: 62782 AN: 152086 Hom.: 15033 Cov.: 31 AF XY: 0.412 AC XY: 30632 AN XY: 74358

African (AFR) AF: 0.167 AC: 6928 AN: 41496

American (AMR) AF: 0.452 AC: 6909 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.371 AC: 1288 AN: 3468

East Asian (EAS) AF: 0.415 AC: 2147 AN: 5174

South Asian (SAS) AF: 0.329 AC: 1586 AN: 4824

European-Finnish (FIN) AF: 0.557 AC: 5887 AN: 10564

Middle Eastern (MID) AF: 0.412 AC: 121 AN: 294

European-Non Finnish (NFE) AF: 0.536 AC: 36448 AN: 67958

Other (OTH) AF: 0.436 AC: 919 AN: 2110

Alfa AF: 0.413 Hom.: 7109

Bravo AF: 0.399

Asia WGS AF: 0.390 AC: 1360 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
CADD	Benign	5.3
DANN	Benign	0.61
PhyloP100		0.020
PromoterAI		-0.081	Neutral
Mutation Taster		=299/1	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs1136774; hg19: chr1-150738197;