9-87725948-C-A

Variant names:

• chr9-87725948-C-A
• rs3118869
• ENST00000676531.1:c.-312C>A

Variant summary

Our verdict is Benign. The variant received -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
• Publications: 16 publications found

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]

ENSG00000304058 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000676531.1. 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
	CTSL	NM_001912.5	MANE Select	c.-461C>A		upstream_gene	N/A	NP_001903.1
	CTSL	NM_001257971.2		c.-371C>A		upstream_gene	N/A	NP_001244900.1
	CTSL	NM_001257972.2		c.-312C>A		upstream_gene	N/A	NP_001244901.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CTSL	ENST00000676531.1		c.-312C>A		5_prime_UTR	Exon 1 of 8	ENSP00000503439.1
	CTSL	ENST00000679149.1		c.-371C>A		5_prime_UTR	Exon 1 of 8	ENSP00000504313.1
	CTSL	ENST00000679157.1		c.-316C>A		5_prime_UTR	Exon 1 of 8	ENSP00000502968.1

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

African (AFR) AF: 0.375 AC: 3 AN: 8

American (AMR) AF: 0.500 AC: 2 AN: 4

Ashkenazi Jewish (ASJ) AF: 0.750 AC: 3 AN: 4

East Asian (EAS) AF: 0.250 AC: 2 AN: 8

South Asian (SAS) AF: 0.375 AC: 3 AN: 8

European-Finnish (FIN) AF: 0.500 AC: 1 AN: 2

Middle Eastern (MID) AF: 0.333 AC: 2 AN: 6

European-Non Finnish (NFE) AF: 0.396 AC: 209 AN: 528

Other (OTH) AF: 0.538 AC: 14 AN: 26

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

African (AFR) AF: 0.487 AC: 20210 AN: 41472

American (AMR) AF: 0.366 AC: 5596 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.504 AC: 1750 AN: 3470

East Asian (EAS) AF: 0.328 AC: 1680 AN: 5124

South Asian (SAS) AF: 0.432 AC: 2079 AN: 4818

European-Finnish (FIN) AF: 0.426 AC: 4514 AN: 10584

Middle Eastern (MID) AF: 0.626 AC: 184 AN: 294

European-Non Finnish (NFE) AF: 0.442 AC: 30047 AN: 67956

Other (OTH) AF: 0.428 AC: 905 AN: 2114

Alfa AF: 0.444 Hom.: 19006

Bravo AF: 0.443

Asia WGS AF: 0.395 AC: 1371 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.76
CADD	Benign	2.5
DANN	Benign	0.69
PhyloP100		-1.4
PromoterAI		-0.23	Neutral
Mutation Taster		=296/4	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: rs3118869; hg19: chr9-90340863;