dbSNP rs1136774: CTSS:c.-25G>A (chr1-150765721-C-T) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

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

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.0200

Publications

22 publications found

Variant links:

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]

CTSS links:

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ACMG classification

Classification was made for transcript

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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CTSS	NM_004079.5 link	c.-25G>A		5_prime_UTR_variant	Exon 1 of 8	ENST00000368985.8	NP_004070.3	P25774-1
CTSS	NM_001199739.2 link	c.-25G>A		5_prime_UTR_variant	Exon 1 of 7		NP_001186668.1	P25774-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CTSS	ENST00000368985.8 link	c.-25G>A		5_prime_UTR_variant	Exon 1 of 8	1	NM_004079.5	ENSP00000357981.3		P25774-1

Frequencies

GnomAD3 genomes

AF:

0.413

AC:

62780

AN:

151968

Hom.:

15034

Cov.:

show subpopulations

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:

AN:

Hom.:

Cov.:

AC XY:

AN XY:

African (AFR)

AC:

AN:

American (AMR)

AC:

AN:

Ashkenazi Jewish (ASJ)

AC:

AN:

East Asian (EAS)

AC:

AN:

South Asian (SAS)

AC:

AN:

European-Finnish (FIN)

AC:

AN:

Middle Eastern (MID)

AC:

AN:

European-Non Finnish (NFE)

AC:

AN:

Other (OTH)

AC:

AN:

GnomAD4 genome

AF:

0.413

AC:

62782

AN:

152086

Hom.:

15033

Cov.:

AF XY:

0.412

AC XY:

30632

AN XY:

74358

show subpopulations

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

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

1699

3398

5098

6797

8496

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

580

1160

1740

2320

2900

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

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 v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.80

CADD

Benign

5.3

(source)

DANN

Benign

0.61

PhyloP100

0.020

PromoterAI

-0.081

Neutral

(source)

Mutation Taster

=299/1

polymorphism (auto)

(source)

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over