chr9-87728350-C-A

Position:

• chr9-87728350-C-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001912.5(CTSL):​c.350C>A​(p.Ser117Tyr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.001 in 1,614,094 control chromosomes in the GnomAD database, including 19 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0055 (11 hom., cov: 32)
  • Exomes 𝑓: 0.00054 (8 hom.)
• Consequence: CTSL NM_001912.5 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 3.16

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]

CTSL (HGNC:):

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.008523166).
• BP6: Variant 9-87728350-C-A is Benign according to our data. Variant chr9-87728350-C-A is described in ClinVar as [Benign]. Clinvar id is 733908.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00546 (832/152260) while in subpopulation AFR AF= 0.0186 (772/41544). AF 95% confidence interval is 0.0175. There are 11 homozygotes in gnomad4. There are 432 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 11 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CTSL	NM_001912.5	c.350C>A	p.Ser117Tyr	missense_variant	4/8	ENST00000343150.10	NP_001903.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CTSL	ENST00000343150.10	c.350C>A	p.Ser117Tyr	missense_variant	4/8	1	NM_001912.5	ENSP00000345344.5

Frequencies

GnomAD3 genomes AF: 0.00534 AC: 813 AN: 152142 Hom.: 9 Cov.: 32

Gnomad AFR AF: 0.0182

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00281

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0000882

Gnomad OTH AF: 0.00478

GnomAD3 exomes AF: 0.00138 AC: 347 AN: 251476 Hom.: 9 AF XY: 0.00111 AC XY: 151 AN XY: 135914

Gnomad AFR exome AF: 0.0191

Gnomad AMR exome AF: 0.000896

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000815

GnomAD4 exome AF: 0.000540 AC: 789 AN: 1461834 Hom.: 8 Cov.: 33 AF XY: 0.000476 AC XY: 346 AN XY: 727220

Gnomad4 AFR exome AF: 0.0188

Gnomad4 AMR exome AF: 0.000917

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000232

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000719

Gnomad4 OTH exome AF: 0.00169

GnomAD4 genome AF: 0.00546 AC: 832 AN: 152260 Hom.: 11 Cov.: 32 AF XY: 0.00580 AC XY: 432 AN XY: 74454

Gnomad4 AFR AF: 0.0186

Gnomad4 AMR AF: 0.00281

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000882

Gnomad4 OTH AF: 0.00473

Alfa AF: 0.00103 Hom.: 1

Bravo AF: 0.00616

ESP6500AA AF: 0.0177 AC: 78

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00164 AC: 199

Asia WGS AF: 0.00346 AC: 12 AN: 3478

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jun 14, 2018	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.51	T
BayesDel_noAF	Benign	-0.48
CADD	Benign	22
DANN	Uncertain	0.98
DEOGEN2	Uncertain	0.76	D;D;D
Eigen	Benign	-0.33
Eigen_PC	Benign	-0.37
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Uncertain	0.96	.;D;D
MetaRNN	Benign	0.0085	T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.4	M;M;.
PrimateAI	Benign	0.46	T
PROVEAN	Uncertain	-2.6	D;D;D
REVEL	Benign	0.071
Sift	Benign	0.29	T;T;T
Sift4G	Benign	0.44	T;T;T
Polyphen		0.15	B;B;.
Vest4		0.47
MVP		0.44
MPC		0.49
ClinPred		0.053	T
GERP RS		2.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.35
gMVP		0.34

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: rs76801214; hg19: chr9-90343265;