dbSNP rs11576175: CTSS:c.399+83C>T (chr1-150754918-G-A) – 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.399+83C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0885 in 1,409,766 control chromosomes in the GnomAD database, including 6,345 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 0.074 ( 590 hom., cov: 32)

Exomes 𝑓: 0.090 ( 5755 hom. )

Consequence

CTSS
NM_004079.5 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.373

Publications

25 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=-0.7).

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.175 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CTSS	NM_004079.5 link	c.399+83C>T		intron_variant	Intron 4 of 7	ENST00000368985.8	NP_004070.3	P25774-1
CTSS	NM_001199739.2 link	c.250-2910C>T		intron_variant	Intron 3 of 6		NP_001186668.1	P25774-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CTSS	ENST00000368985.8 link	c.399+83C>T		intron_variant	Intron 4 of 7	1	NM_004079.5	ENSP00000357981.3		P25774-1

Frequencies

GnomAD3 genomes

AF:

0.0741

AC:

11275

AN:

152110

Hom.:

587

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0141

Gnomad AMI

AF:

0.130

Gnomad AMR

AF:

0.0664

Gnomad ASJ

AF:

0.145

Gnomad EAS

AF:

0.183

Gnomad SAS

AF:

0.106

Gnomad FIN

AF:

0.0960

Gnomad MID

AF:

0.117

Gnomad NFE

AF:

0.0938

Gnomad OTH

AF:

0.0759

GnomAD4 exome

AF:

0.0902

AC:

113460

AN:

1257538

Hom.:

5755

AF XY:

0.0916

AC XY:

56860

AN XY:

620860

show subpopulations

African (AFR)

AF:

0.0114

AC:

323

AN:

28262

American (AMR)

AF:

0.0586

AC:

1769

AN:

30184

Ashkenazi Jewish (ASJ)

AF:

0.155

AC:

3041

AN:

19646

East Asian (EAS)

AF:

0.184

AC:

6962

AN:

37892

South Asian (SAS)

AF:

0.114

AC:

7578

AN:

66524

European-Finnish (FIN)

AF:

0.0954

AC:

4730

AN:

49596

Middle Eastern (MID)

AF:

0.121

AC:

607

AN:

5026

European-Non Finnish (NFE)

AF:

0.0865

AC:

83706

AN:

967856

Other (OTH)

AF:

0.0903

AC:

4744

AN:

52552

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.515

Heterozygous variant carriers

4959

9919

14878

19838

24797

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.0741

AC:

11287

AN:

152228

Hom.:

590

Cov.:

AF XY:

0.0746

AC XY:

5551

AN XY:

74420

show subpopulations

African (AFR)

AF:

0.0141

AC:

585

AN:

41550

American (AMR)

AF:

0.0667

AC:

1020

AN:

15300

Ashkenazi Jewish (ASJ)

AF:

0.145

AC:

502

AN:

3472

East Asian (EAS)

AF:

0.184

AC:

954

AN:

5178

South Asian (SAS)

AF:

0.106

AC:

510

AN:

4814

European-Finnish (FIN)

AF:

0.0960

AC:

1016

AN:

10586

Middle Eastern (MID)

AF:

0.122

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0938

AC:

6381

AN:

68006

Other (OTH)

AF:

0.0775

AC:

164

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

528

1056

1583

2111

2639

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.0880

Hom.:

1910

Bravo

AF:

0.0716

Asia WGS

AF:

0.143

AC:

495

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.70

CADD

Benign

4.7

(source)

DANN

Benign

0.77

PhyloP100

0.37

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

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rs11576175

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over