9-87728764-T-A

Position:

• chr9-87728764-T-A

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Moderate BP6_Moderate

The NM_001912.5(CTSL):​c.576T>A​(p.Asp192Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: CTSL NM_001912.5 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.0890

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 Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.08647713).
• BP6: Variant 9-87728764-T-A is Benign according to our data. Variant chr9-87728764-T-A is described in ClinVar as [Likely_benign]. Clinvar id is 3270231.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CTSL	NM_001912.5	c.576T>A	p.Asp192Glu	missense_variant	5/8	ENST00000343150.10	NP_001903.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CTSL	ENST00000343150.10	c.576T>A	p.Asp192Glu	missense_variant	5/8	1	NM_001912.5	ENSP00000345344.5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 30, 2024

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.34	T
BayesDel_noAF	Benign	-0.72
CADD	Benign	0.58
DANN	Benign	0.43
DEOGEN2	Uncertain	0.59	D;D;T
Eigen	Benign	-1.7
Eigen_PC	Benign	-1.7
FATHMM_MKL	Benign	0.51	D
LIST_S2	Benign	0.26	.;T;T
M_CAP	Benign	0.0015	T
MetaRNN	Benign	0.086	T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.015	N;N;.
PrimateAI	Benign	0.36	T
PROVEAN	Benign	-1.4	N;N;N
REVEL	Benign	0.19
Sift	Benign	0.50	T;T;T
Sift4G	Benign	0.38	T;T;T
Polyphen		0.0	B;B;.
Vest4		0.082
MutPred		0.40		Gain of phosphorylation at Y189 (P = 0.1297);Gain of phosphorylation at Y189 (P = 0.1297);Gain of phosphorylation at Y189 (P = 0.1297);
MVP		0.11
MPC		0.077
ClinPred		0.062	T
GERP RS		-7.5
Varity_R		0.19
gMVP		0.19

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr9-90343679;