rs41271951

Positions:

• chr1-150764744-A-G

Variant summary

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

The ENST00000368985.8(CTSS):​c.20T>C​(p.Val7Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0686 in 1,613,994 control chromosomes in the GnomAD database, including 4,371 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.050 (256 hom., cov: 31)
  • Exomes 𝑓: 0.071 (4115 hom.)
• Consequence: CTSS ENST00000368985.8 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0450

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 (MetaRNN=0.003063053).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0758 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CTSS	NM_004079.5	c.20T>C	p.Val7Ala	missense_variant	2/8	ENST00000368985.8	NP_004070.3
CTSS	NM_001199739.2	c.20T>C	p.Val7Ala	missense_variant	2/7		NP_001186668.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CTSS	ENST00000368985.8	c.20T>C	p.Val7Ala	missense_variant	2/8	1	NM_004079.5	ENSP00000357981	P1

Frequencies

GnomAD3 genomes AF: 0.0505 AC: 7687 AN: 152170 Hom.: 256 Cov.: 31

Gnomad AFR AF: 0.0142

Gnomad AMI AF: 0.0373

Gnomad AMR AF: 0.0413

Gnomad ASJ AF: 0.0551

Gnomad EAS AF: 0.000384

Gnomad SAS AF: 0.0122

Gnomad FIN AF: 0.0743

Gnomad MID AF: 0.0475

Gnomad NFE AF: 0.0775

Gnomad OTH AF: 0.0506

GnomAD3 exomes AF: 0.0506 AC: 12704 AN: 251284 Hom.: 416 AF XY: 0.0505 AC XY: 6862 AN XY: 135826

Gnomad AFR exome AF: 0.0127

Gnomad AMR exome AF: 0.0264

Gnomad ASJ exome AF: 0.0588

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0153

Gnomad FIN exome AF: 0.0710

Gnomad NFE exome AF: 0.0758

Gnomad OTH exome AF: 0.0611

GnomAD4 exome AF: 0.0705 AC: 103085 AN: 1461706 Hom.: 4115 Cov.: 31 AF XY: 0.0688 AC XY: 50026 AN XY: 727150

Gnomad4 AFR exome AF: 0.0113

Gnomad4 AMR exome AF: 0.0285

Gnomad4 ASJ exome AF: 0.0593

Gnomad4 EAS exome AF: 0.0000504

Gnomad4 SAS exome AF: 0.0158

Gnomad4 FIN exome AF: 0.0664

Gnomad4 NFE exome AF: 0.0816

Gnomad4 OTH exome AF: 0.0667

GnomAD4 genome AF: 0.0505 AC: 7686 AN: 152288 Hom.: 256 Cov.: 31 AF XY: 0.0490 AC XY: 3646 AN XY: 74468

Gnomad4 AFR AF: 0.0141

Gnomad4 AMR AF: 0.0412

Gnomad4 ASJ AF: 0.0551

Gnomad4 EAS AF: 0.000385

Gnomad4 SAS AF: 0.0126

Gnomad4 FIN AF: 0.0743

Gnomad4 NFE AF: 0.0775

Gnomad4 OTH AF: 0.0501

Alfa AF: 0.0721 Hom.: 705

Bravo AF: 0.0472

TwinsUK AF: 0.0747 AC: 277

ALSPAC AF: 0.0784 AC: 302

ESP6500AA AF: 0.0150 AC: 66

ESP6500EA AF: 0.0815 AC: 701

ExAC AF: 0.0502 AC: 6091

Asia WGS AF: 0.00837 AC: 29 AN: 3478

EpiCase AF: 0.0765

EpiControl AF: 0.0717

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.59	T
BayesDel_noAF	Benign	-0.57
CADD	Benign	3.3
DANN	Benign	0.70
DEOGEN2	Benign	0.14	T;.
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.4
FATHMM_MKL	Benign	0.27	N
LIST_S2	Benign	0.39	T;T
MetaRNN	Benign	0.0031	T;T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	0.64	N;N
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.28	T
PROVEAN	Benign	-1.1	N;N
REVEL	Benign	0.24
Sift	Benign	0.42	T;T
Sift4G	Benign	0.30	T;T
Polyphen		0.0	B;.
Vest4		0.037
MPC		0.66
ClinPred		0.0024	T
GERP RS		-1.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Varity_R		0.035
gMVP		0.53

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: rs41271951; hg19: chr1-150737220; COSMIC: COSV64566328; COSMIC: COSV64566328;