20-23637790-C-G

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM1BP4_Moderate

The NM_000099.4(CST3):c.73G>C(p.Ala25Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A25T) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

CST3
NM_000099.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.602

Publications

87 publications found

Variant links:

Genes affected

CST3 (HGNC:2475): (cystatin C) The cystatin superfamily encompasses proteins that contain multiple cystatin-like sequences. Some of the members are active cysteine protease inhibitors, while others have lost or perhaps never acquired this inhibitory activity. There are three inhibitory families in the superfamily, including the type 1 cystatins (stefins), type 2 cystatins and the kininogens. The type 2 cystatin proteins are a class of cysteine proteinase inhibitors found in a variety of human fluids and secretions, where they appear to provide protective functions. The cystatin locus on chromosome 20 contains the majority of the type 2 cystatin genes and pseudogenes. This gene is located in the cystatin locus and encodes the most abundant extracellular inhibitor of cysteine proteases, which is found in high concentrations in biological fluids and is expressed in virtually all organs of the body. A mutation in this gene has been associated with amyloid angiopathy. Expression of this protein in vascular wall smooth muscle cells is severely reduced in both atherosclerotic and aneurysmal aortic lesions, establishing its role in vascular disease. In addition, this protein has been shown to have an antimicrobial function, inhibiting the replication of herpes simplex virus. Alternative splicing results in multiple transcript variants encoding a single protein. [provided by RefSeq, Nov 2014]

CST3 Gene-Disease associations (from GenCC):

ACys amyloidosis
Inheritance: AD Classification: STRONG, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae)

CST3 links:

ENSG00000286117 (HGNC:):

ENSG00000286117 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

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

PM1

In a mutagenesis_site Shows a dual distribution to the Golgi apparatus and to the mitochondria. (size 0) in uniprot entity CYTC_HUMAN

BP4

Computational evidence support a benign effect (MetaRNN=0.08239013).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CST3	NM_000099.4 link	c.73G>C	p.Ala25Pro	missense_variant	Exon 1 of 3	ENST00000376925.8	NP_000090.1	P01034A0A0K0K1J1
CST3	NM_001288614.2 link	c.73G>C	p.Ala25Pro	missense_variant	Exon 1 of 4		NP_001275543.1	P01034A0A0K0K1J1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
CST3	ENST00000376925.8 link	c.73G>C	p.Ala25Pro	missense_variant	Exon 1 of 3	1	NM_000099.4	ENSP00000366124.3	P01034
CST3	ENST00000398411.5 link	c.73G>C	p.Ala25Pro	missense_variant	Exon 1 of 4	1		ENSP00000381448.1	P01034
CST3	ENST00000398409.1 link	c.73G>C	p.Ala25Pro	missense_variant	Exon 2 of 4	3		ENSP00000381446.1	P01034
ENSG00000286117	ENST00000801340.1 link	n.120+280C>G		intron_variant	Intron 1 of 3

Frequencies

GnomAD3 genomes

AF:

0.00

AC:

AN:

152056

Hom.:

Cov.:

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD4 exome

Data not reliable, filtered out with message: AC0;AS_VQSR

AF:

0.00

AC:

AN:

1371788

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

676234

African (AFR)

AF:

0.00

AC:

AN:

28104

American (AMR)

AF:

0.00

AC:

AN:

33126

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

24150

East Asian (EAS)

AF:

0.00

AC:

AN:

32474

South Asian (SAS)

AF:

0.00

AC:

AN:

76584

European-Finnish (FIN)

AF:

0.00

AC:

AN:

47822

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4014

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1068816

Other (OTH)

AF:

0.00

AC:

AN:

56698

GnomAD4 genome

Data not reliable, filtered out with message: AC0;AS_VQSR

AF:

0.00

AC:

AN:

152162

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74398

African (AFR)

AF:

0.00

AC:

AN:

41530

American (AMR)

AF:

0.00

AC:

AN:

15300

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5152

South Asian (SAS)

AF:

0.00

AC:

AN:

4834

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10606

Middle Eastern (MID)

AF:

0.00

AC:

AN:

290

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

67956

Other (OTH)

AF:

0.00

AC:

AN:

2112

Alfa

AF:

0.00

Hom.:

1036

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.077

BayesDel_addAF

Benign

-0.30

BayesDel_noAF

Benign

-0.66

CADD

Benign

5.9

(source)

DANN

Benign

0.78

DEOGEN2

Benign

0.28

T;T;T

Eigen

Benign

-1.3

Eigen_PC

Benign

-1.3

FATHMM_MKL

Benign

0.26

LIST_S2

Benign

0.34

.;.;T

M_CAP

Benign

0.0030

MetaRNN

Benign

0.082

T;T;T

MetaSVM

Benign

-0.95

MutationAssessor

Benign

0.90

L;L;L

PhyloP100

-0.60

PrimateAI

Uncertain

0.73

PROVEAN

Benign

-1.6

N;N;N

REVEL

Benign

0.011

Sift

Benign

0.13

T;T;T

Sift4G

Uncertain

0.021

D;D;D

Polyphen

0.0030

B;B;B

Vest4

0.15

MutPred

0.29

Gain of glycosylation at A25 (P = 0.0072);Gain of glycosylation at A25 (P = 0.0072);Gain of glycosylation at A25 (P = 0.0072);

MVP

0.14

MPC

0.56

ClinPred

0.017

GERP RS

-1.6

PromoterAI

-0.032

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.21

gMVP

0.64

Mutation Taster

=97/3

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over