Genetic Variant NM_001334.3:c.646A>G (chr4-155937390-T-C) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_001334.3(CTSO):c.646A>G(p.Ile216Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000686 in 1,458,434 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 17/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000069 ( 0 hom. )

Consequence

CTSO
NM_001334.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.15

Publications

0 publications found

Variant links:

Genes affected

CTSO (HGNC:2542): (cathepsin O) The protein encoded by the gene is a cysteine proteinase and a member of the papain superfamily. This proteolytic enzyme is involved in cellular protein degradation and turnover. The recombinant form of this enzyme was shown to degrade synthetic peptides typically used as substrates for cysteine proteinases and its proteolytic activity was abolished by an inhibitor of cyteine proteinase. [provided by RefSeq, Jul 2008]

CTSO links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.09890857).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001334.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CTSO	NM_001334.3	MANE Select	c.646A>G	p.Ile216Val	missense	Exon 5 of 8	NP_001325.1	P43234

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
CTSO	ENST00000433477.4	TSL:1 MANE Select	c.646A>G	p.Ile216Val	missense	Exon 5 of 8	ENSP00000414904.3	P43234
CTSO	ENST00000679996.1		c.646A>G	p.Ile216Val	missense	Exon 5 of 9	ENSP00000505550.1	A0A7P0T996
CTSO	ENST00000680741.1		c.646A>G	p.Ile216Val	missense	Exon 5 of 8	ENSP00000505756.1	A0A7P0Z4C4

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000398

AC:

AN:

250998

AF XY:

0.00

show subpopulations

Gnomad AFR exome

AF:

0.0000618

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000686

AC:

AN:

1458434

Hom.:

Cov.:

AF XY:

0.00000827

AC XY:

AN XY:

725728

show subpopulations

African (AFR)

AF:

0.000120

AC:

AN:

33398

American (AMR)

AF:

0.00

AC:

AN:

44710

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26104

East Asian (EAS)

AF:

0.00

AC:

AN:

39640

South Asian (SAS)

AF:

0.00

AC:

AN:

86162

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53406

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5756

European-Non Finnish (NFE)

AF:

0.00000541

AC:

AN:

1108974

Other (OTH)

AF:

0.00

AC:

AN:

60284

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.410

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

Alfa

AF:

0.0000370

Hom.:

Bravo

AF:

0.0000113

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.071

BayesDel_addAF

Benign

-0.26

BayesDel_noAF

Benign

-0.43

CADD

Benign

(source)

DANN

Benign

0.81

DEOGEN2

Benign

0.25

Eigen

Benign

-0.59

Eigen_PC

Benign

-0.37

FATHMM_MKL

Uncertain

0.86

M_CAP

Benign

0.013

MetaRNN

Benign

0.099

MetaSVM

Benign

-0.77

MutationAssessor

Benign

-0.17

PhyloP100

3.1

PrimateAI

Benign

0.31

PROVEAN

Benign

-0.22

REVEL

Benign

0.20

Sift

Benign

0.43

Sift4G

Benign

0.40

Polyphen

0.0060

Vest4

0.20

MVP

0.66

MPC

0.062

ClinPred

0.034

GERP RS

2.7

Varity_R

0.033

gMVP

0.33

Mutation Taster

=93/7

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

Details are displayed if max score is > 0.2

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

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over