rs3118869

Positions:

• chr9-87725948-C-A
• chr9-87725948-C-G

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The ENST00000676531.1(CTSL):​c.-312C>A variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.442 in 152,630 control chromosomes in the GnomAD database, including 15,090 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 0.44 (15042 hom., cov: 32)
  • Exomes 𝑓: 0.40 (48 hom.)
• Consequence: CTSL ENST00000676531.1 5_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.45

Genes affected

CTSL (HGNC:2537): (cathepsin L) The protein encoded by this gene is a lysosomal cysteine proteinase that plays a major role in intracellular protein catabolism. Its substrates include collagen and elastin, as well as alpha-1 protease inhibitor, a major controlling element of neutrophil elastase activity. The encoded protein has been implicated in several pathologic processes, including myofibril necrosis in myopathies and in myocardial ischemia, and in the renal tubular response to proteinuria. This protein, which is a member of the peptidase C1 family, is a dimer composed of disulfide-linked heavy and light chains, both produced from a single protein precursor. Additionally, this protein cleaves the S1 subunit of the SARS-CoV-2 spike protein, which is necessary for entry of the virus into the cell. [provided by RefSeq, Aug 2020]

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.76).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.482 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CTSL	ENST00000676531.1	c.-312C>A		5_prime_UTR_variant	1/8			P1
CTSL	ENST00000679149.1	c.-371C>A		5_prime_UTR_variant	1/8			P1
CTSL	ENST00000679157.1	c.-316C>A		5_prime_UTR_variant	1/8			P1

Frequencies

GnomAD3 genomes AF: 0.443 AC: 67256 AN: 151916 Hom.: 15034 Cov.: 32

Gnomad AFR AF: 0.487

Gnomad AMI AF: 0.353

Gnomad AMR AF: 0.366

Gnomad ASJ AF: 0.504

Gnomad EAS AF: 0.328

Gnomad SAS AF: 0.432

Gnomad FIN AF: 0.426

Gnomad MID AF: 0.633

Gnomad NFE AF: 0.442

Gnomad OTH AF: 0.430

GnomAD4 exome AF: 0.402 AC: 239 AN: 594 Hom.: 48 Cov.: 0 AF XY: 0.421 AC XY: 196 AN XY: 466

Gnomad4 AFR exome AF: 0.375

Gnomad4 AMR exome AF: 0.500

Gnomad4 ASJ exome AF: 0.750

Gnomad4 EAS exome AF: 0.250

Gnomad4 SAS exome AF: 0.375

Gnomad4 FIN exome AF: 0.500

Gnomad4 NFE exome AF: 0.396

Gnomad4 OTH exome AF: 0.538

GnomAD4 genome AF: 0.443 AC: 67287 AN: 152036 Hom.: 15042 Cov.: 32 AF XY: 0.440 AC XY: 32662 AN XY: 74310

Gnomad4 AFR AF: 0.487

Gnomad4 AMR AF: 0.366

Gnomad4 ASJ AF: 0.504

Gnomad4 EAS AF: 0.328

Gnomad4 SAS AF: 0.432

Gnomad4 FIN AF: 0.426

Gnomad4 NFE AF: 0.442

Gnomad4 OTH AF: 0.428

Alfa AF: 0.445 Hom.: 14349

Bravo AF: 0.443

Asia WGS AF: 0.395 AC: 1371 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.76
CADD	Benign	2.5
DANN	Benign	0.69

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

Publications

LitVar

Other links and lift over

dbSNP: rs3118869; hg19: chr9-90340863;