rs7418501

Variant names:

• chr1-150739420-A-T
• rs7418501
• NM_004079.5:c.897-6275T>A

Variant summary

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

The NM_004079.5(CTSS):​c.897-6275T>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.386 in 151,756 control chromosomes in the GnomAD database, including 11,589 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 0.39 (11589 hom., cov: 32)
• Consequence: CTSS NM_004079.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -2.79
• Publications: 11 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=-1.04).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.533 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CTSS	NM_004079.5	c.897-6275T>A		intron_variant	Intron 7 of 7	ENST00000368985.8	NP_004070.3
CTSS	NM_001199739.2	c.747-6275T>A		intron_variant	Intron 6 of 6		NP_001186668.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CTSS	ENST00000368985.8	c.897-6275T>A		intron_variant	Intron 7 of 7	1	NM_004079.5	ENSP00000357981.3

Frequencies

GnomAD3 genomes AF: 0.386 AC: 58513 AN: 151638 Hom.: 11579 Cov.: 32

Gnomad AFR AF: 0.309

Gnomad AMI AF: 0.268

Gnomad AMR AF: 0.436

Gnomad ASJ AF: 0.492

Gnomad EAS AF: 0.359

Gnomad SAS AF: 0.551

Gnomad FIN AF: 0.400

Gnomad MID AF: 0.429

Gnomad NFE AF: 0.405

Gnomad OTH AF: 0.394

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

GnomAD4 genome AF: 0.386 AC: 58541 AN: 151756 Hom.: 11589 Cov.: 32 AF XY: 0.390 AC XY: 28947 AN XY: 74156

African (AFR) AF: 0.309 AC: 12774 AN: 41386

American (AMR) AF: 0.435 AC: 6642 AN: 15256

Ashkenazi Jewish (ASJ) AF: 0.492 AC: 1707 AN: 3468

East Asian (EAS) AF: 0.359 AC: 1833 AN: 5100

South Asian (SAS) AF: 0.550 AC: 2646 AN: 4808

European-Finnish (FIN) AF: 0.400 AC: 4227 AN: 10556

Middle Eastern (MID) AF: 0.421 AC: 122 AN: 290

European-Non Finnish (NFE) AF: 0.405 AC: 27507 AN: 67874

Other (OTH) AF: 0.398 AC: 839 AN: 2108

Alfa AF: 0.393 Hom.: 1486

Bravo AF: 0.377

Asia WGS AF: 0.393 AC: 1365 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-1.0
CADD	Benign	0.41
DANN	Benign	0.32
PhyloP100		-2.8
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: rs7418501; hg19: chr1-150711896;