NM_004079.5:c.249+351C>T

Variant names:

• chr1-150757507-G-A
• rs10888391
• NM_004079.5:c.249+351C>T

Variant summary

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

The NM_004079.5(CTSS):​c.249+351C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.352 in 151,758 control chromosomes in the GnomAD database, including 9,774 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 (9774 hom., cov: 31)
• Consequence: CTSS NM_004079.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.232
• 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=-0.93).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.52 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CTSS	NM_004079.5	c.249+351C>T		intron_variant	Intron 3 of 7	ENST00000368985.8	NP_004070.3
CTSS	NM_001199739.2	c.249+351C>T		intron_variant	Intron 3 of 6		NP_001186668.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CTSS	ENST00000368985.8	c.249+351C>T		intron_variant	Intron 3 of 7	1	NM_004079.5	ENSP00000357981.3

Frequencies

GnomAD3 genomes AF: 0.353 AC: 53464 AN: 151640 Hom.: 9768 Cov.: 31

Gnomad AFR AF: 0.276

Gnomad AMI AF: 0.265

Gnomad AMR AF: 0.416

Gnomad ASJ AF: 0.476

Gnomad EAS AF: 0.356

Gnomad SAS AF: 0.538

Gnomad FIN AF: 0.349

Gnomad MID AF: 0.414

Gnomad NFE AF: 0.367

Gnomad OTH AF: 0.359

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

GnomAD4 genome AF: 0.352 AC: 53484 AN: 151758 Hom.: 9774 Cov.: 31 AF XY: 0.357 AC XY: 26498 AN XY: 74136

African (AFR) AF: 0.275 AC: 11388 AN: 41340

American (AMR) AF: 0.416 AC: 6341 AN: 15252

Ashkenazi Jewish (ASJ) AF: 0.476 AC: 1649 AN: 3466

East Asian (EAS) AF: 0.356 AC: 1842 AN: 5172

South Asian (SAS) AF: 0.537 AC: 2582 AN: 4808

European-Finnish (FIN) AF: 0.349 AC: 3662 AN: 10494

Middle Eastern (MID) AF: 0.404 AC: 118 AN: 292

European-Non Finnish (NFE) AF: 0.367 AC: 24895 AN: 67916

Other (OTH) AF: 0.363 AC: 766 AN: 2110

Alfa AF: 0.357 Hom.: 12568

Bravo AF: 0.347

Asia WGS AF: 0.383 AC: 1332 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.93
CADD	Benign	1.1
DANN	Benign	0.63
PhyloP100		-0.23
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: rs10888391; hg19: chr1-150729983;