Variant rs1064039 details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 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. 14/21 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 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

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 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/exons	MANE	Protein	UniProt
CST3	NM_000099.4 linkuse as main transcript	c.73G>C	p.Ala25Pro	missense_variant	1/3	ENST00000376925.8	NP_000090.1	P01034A0A0K0K1J1
CST3	NM_001288614.2 linkuse as main transcript	c.73G>C	p.Ala25Pro	missense_variant	1/4		NP_001275543.1	P01034A0A0K0K1J1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
CST3	ENST00000376925.8 linkuse as main transcript	c.73G>C	p.Ala25Pro	missense_variant	1/3	1	NM_000099.4	ENSP00000366124.3	P01034
CST3	ENST00000398411.5 linkuse as main transcript	c.73G>C	p.Ala25Pro	missense_variant	1/4	1		ENSP00000381448.1	P01034
CST3	ENST00000398409.1 linkuse as main transcript	c.73G>C	p.Ala25Pro	missense_variant	2/4	3		ENSP00000381446.1	P01034

Frequencies

GnomAD3 genomes

AF:

0.00

AC:

AN:

152056

Hom.:

Cov.:

FAILED QC

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

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

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

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

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

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

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

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.21

gMVP

0.64

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

LitVar

Other links and lift over