1-150764744-A-G

Variant names:

• chr1-150764744-A-G
• rs41271951
• NM_004079.5:c.20T>C

Variant summary

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

The NM_004079.5(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. 16/21 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 NM_004079.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0450
• Publications: 39 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 (MetaRNN=0.003063053).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0758 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.20T>C	p.Val7Ala	missense	Exon 2 of 8	NP_004070.3
	CTSS	NM_001199739.2		c.20T>C	p.Val7Ala	missense	Exon 2 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.20T>C	p.Val7Ala	missense	Exon 2 of 8	ENSP00000357981.3
	CTSS	ENST00000679512.1		c.20T>C	p.Val7Ala	missense	Exon 2 of 7	ENSP00000505113.1
	CTSS	ENST00000680288.1		c.20T>C	p.Val7Ala	missense	Exon 2 of 7	ENSP00000506001.1

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

GnomAD2 exomes AF: 0.0506 AC: 12704 AN: 251284 AF XY: 0.0505

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 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

African (AFR) AF: 0.0113 AC: 378 AN: 33474

American (AMR) AF: 0.0285 AC: 1276 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.0593 AC: 1550 AN: 26132

East Asian (EAS) AF: 0.0000504 AC: 2 AN: 39694

South Asian (SAS) AF: 0.0158 AC: 1360 AN: 86258

European-Finnish (FIN) AF: 0.0664 AC: 3545 AN: 53404

Middle Eastern (MID) AF: 0.0456 AC: 263 AN: 5768

European-Non Finnish (NFE) AF: 0.0816 AC: 90685 AN: 1111866

Other (OTH) AF: 0.0667 AC: 4026 AN: 60392

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

African (AFR) AF: 0.0141 AC: 588 AN: 41568

American (AMR) AF: 0.0412 AC: 630 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.0551 AC: 191 AN: 3466

East Asian (EAS) AF: 0.000385 AC: 2 AN: 5190

South Asian (SAS) AF: 0.0126 AC: 61 AN: 4830

European-Finnish (FIN) AF: 0.0743 AC: 788 AN: 10610

Middle Eastern (MID) AF: 0.0476 AC: 14 AN: 294

European-Non Finnish (NFE) AF: 0.0775 AC: 5272 AN: 68020

Other (OTH) AF: 0.0501 AC: 106 AN: 2116

Alfa AF: 0.0667 Hom.: 922

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 v4.9

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
MetaRNN	Benign	0.0031	T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	0.64	N
PhyloP100		-0.045
PrimateAI	Benign	0.28	T
PROVEAN	Benign	-1.1	N
REVEL	Benign	0.24
Sift	Benign	0.42	T
Sift4G	Benign	0.30	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
Mutation Taster		=99/1	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: rs41271951; hg19: chr1-150737220; COSMIC: COSV64566328; COSMIC: COSV64566328;