1-150735160-A-T

Variant names:

• chr1-150735160-A-T
• rs7511673
• NM_004079.5:c.897-2015T>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.897-2015T>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.377 in 152,046 control chromosomes in the GnomAD database, including 11,074 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 0.38 (11074 hom., cov: 32)
• Consequence: CTSS NM_004079.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.219
• Publications: 10 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=-0.87).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.524 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.897-2015T>A		intron	N/A	NP_004070.3
	CTSS	NM_001199739.2		c.747-2015T>A		intron	N/A	NP_001186668.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CTSS	ENST00000368985.8	TSL:1 MANE Select	c.897-2015T>A		intron	N/A	ENSP00000357981.3
	CTSS	ENST00000679512.1		c.794-2015T>A		intron	N/A	ENSP00000505113.1
	CTSS	ENST00000680288.1		c.747-2015T>A		intron	N/A	ENSP00000506001.1

Frequencies

GnomAD3 genomes AF: 0.377 AC: 57305 AN: 151928 Hom.: 11065 Cov.: 32

Gnomad AFR AF: 0.306

Gnomad AMI AF: 0.268

Gnomad AMR AF: 0.425

Gnomad ASJ AF: 0.450

Gnomad EAS AF: 0.356

Gnomad SAS AF: 0.542

Gnomad FIN AF: 0.399

Gnomad MID AF: 0.427

Gnomad NFE AF: 0.394

Gnomad OTH AF: 0.380

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

GnomAD4 genome AF: 0.377 AC: 57332 AN: 152046 Hom.: 11074 Cov.: 32 AF XY: 0.382 AC XY: 28382 AN XY: 74332

African (AFR) AF: 0.306 AC: 12672 AN: 41464

American (AMR) AF: 0.424 AC: 6477 AN: 15268

Ashkenazi Jewish (ASJ) AF: 0.450 AC: 1560 AN: 3470

East Asian (EAS) AF: 0.357 AC: 1846 AN: 5172

South Asian (SAS) AF: 0.541 AC: 2614 AN: 4828

European-Finnish (FIN) AF: 0.399 AC: 4212 AN: 10562

Middle Eastern (MID) AF: 0.418 AC: 122 AN: 292

European-Non Finnish (NFE) AF: 0.394 AC: 26773 AN: 67968

Other (OTH) AF: 0.385 AC: 813 AN: 2114

Alfa AF: 0.384 Hom.: 1418

Bravo AF: 0.368

Asia WGS AF: 0.390 AC: 1356 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	4.2
DANN	Benign	0.56
PhyloP100		0.22
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: rs7511673; hg19: chr1-150707636; COSMIC: COSV64566972; COSMIC: COSV64566972;