1-150751271-T-C

Variant names:

• chr1-150751271-T-C
• rs3768018
• NM_004079.5:c.627+510A>G

Variant summary

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

The NM_004079.5(CTSS):​c.627+510A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.354 in 151,914 control chromosomes in the GnomAD database, including 9,854 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 0.35 (9854 hom., cov: 30)
• Consequence: CTSS NM_004079.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -3.31
• Publications: 16 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=-0.98).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.518 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CTSS	NM_004079.5	c.627+510A>G		intron_variant	Intron 5 of 7	ENST00000368985.8	NP_004070.3
CTSS	NM_001199739.2	c.477+510A>G		intron_variant	Intron 4 of 6		NP_001186668.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CTSS	ENST00000368985.8	c.627+510A>G		intron_variant	Intron 5 of 7	1	NM_004079.5	ENSP00000357981.3

Frequencies

GnomAD3 genomes AF: 0.354 AC: 53771 AN: 151794 Hom.: 9845 Cov.: 30

Gnomad AFR AF: 0.283

Gnomad AMI AF: 0.266

Gnomad AMR AF: 0.416

Gnomad ASJ AF: 0.473

Gnomad EAS AF: 0.355

Gnomad SAS AF: 0.536

Gnomad FIN AF: 0.347

Gnomad MID AF: 0.408

Gnomad NFE AF: 0.367

Gnomad OTH AF: 0.361

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.354 AC: 53799 AN: 151914 Hom.: 9854 Cov.: 30 AF XY: 0.359 AC XY: 26649 AN XY: 74224

African (AFR) AF: 0.283 AC: 11709 AN: 41430

American (AMR) AF: 0.416 AC: 6355 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.473 AC: 1642 AN: 3472

East Asian (EAS) AF: 0.355 AC: 1826 AN: 5142

South Asian (SAS) AF: 0.536 AC: 2578 AN: 4814

European-Finnish (FIN) AF: 0.347 AC: 3655 AN: 10536

Middle Eastern (MID) AF: 0.401 AC: 118 AN: 294

European-Non Finnish (NFE) AF: 0.367 AC: 24902 AN: 67932

Other (OTH) AF: 0.366 AC: 771 AN: 2108

Alfa AF: 0.356 Hom.: 1598

Bravo AF: 0.349

Asia WGS AF: 0.379 AC: 1317 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.98
CADD	Benign	0.19
DANN	Benign	0.27
PhyloP100		-3.3
Mutation Taster		=100/0	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: rs3768018; hg19: chr1-150723747;