Variant 3-184849118-G-A details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_001009921.3(VPS8):c.589G>A(p.Gly197Ser) variant causes a missense change. The variant allele was found at a frequency of 0.0000917 in 1,613,480 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00039 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000060 ( 0 hom. )

Consequence

VPS8
NM_001009921.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 5.55

Variant links:

Genes affected

VPS8 (HGNC:29122): (VPS8 subunit of CORVET complex) Predicted to enable metal ion binding activity. Involved in endosomal vesicle fusion. Located in early endosome. [provided by Alliance of Genome Resources, Apr 2022]

VPS8 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

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=0.029780537).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
VPS8	NM_001009921.3 linkuse as main transcript	c.589G>A	p.Gly197Ser	missense_variant	9/48	ENST00000625842.3	NP_001009921.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
VPS8	ENST00000625842.3 linkuse as main transcript	c.589G>A	p.Gly197Ser	missense_variant	9/48	5	NM_001009921.3	ENSP00000487164	A1	Q8N3P4-1

Frequencies

GnomAD3 genomes

AF:

0.000388

AC:

AN:

152088

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00128

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000655

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:

0.0000441

Gnomad OTH

AF:

0.000959

GnomAD3 exomes

AF:

0.0000843

AC:

AN:

249034

Hom.:

AF XY:

0.0000592

AC XY:

AN XY:

135090

show subpopulations

Gnomad AFR exome

AF:

0.00110

Gnomad AMR exome

AF:

0.0000580

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000327

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.000165

GnomAD4 exome

AF:

0.0000602

AC:

AN:

1461274

Hom.:

Cov.:

AF XY:

0.0000454

AC XY:

AN XY:

726932

show subpopulations

Gnomad4 AFR exome

AF:

0.00167

Gnomad4 AMR exome

AF:

0.000134

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000348

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000630

Gnomad4 OTH exome

AF:

0.000232

GnomAD4 genome

AF:

0.000394

AC:

AN:

152206

Hom.:

Cov.:

AF XY:

0.000282

AC XY:

AN XY:

74418

show subpopulations

Gnomad4 AFR

AF:

0.00130

Gnomad4 AMR

AF:

0.0000654

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000441

Gnomad4 OTH

AF:

0.000949

Alfa

AF:

0.0000952

Hom.:

Bravo

AF:

0.000521

ESP6500AA

AF:

0.000509

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.0000827

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3478

EpiCase

AF:

0.00

EpiControl

AF:

0.0000593

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 22, 2021

The c.589G>A (p.G197S) alteration is located in exon 9 (coding exon 8) of the VPS8 gene. This alteration results from a G to A substitution at nucleotide position 589, causing the glycine (G) at amino acid position 197 to be replaced by a serine (S). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.062

BayesDel_addAF

Benign

-0.31

BayesDel_noAF

Benign

-0.26

CADD

Benign

DANN

Benign

0.90

DEOGEN2

Benign

0.0035

.;.;.;T;T

Eigen

Benign

-0.31

Eigen_PC

Benign

-0.10

FATHMM_MKL

Uncertain

0.92

LIST_S2

Benign

0.84

T;T;D;D;T

M_CAP

Benign

0.036

MetaRNN

Benign

0.030

T;T;T;T;T

MetaSVM

Benign

-0.45

MutationAssessor

Benign

-1.4

.;.;.;.;N

MutationTaster

Benign

0.99

D;D;D;N

PrimateAI

Benign

0.48

PROVEAN

Benign

0.90

N;N;N;N;.

REVEL

Benign

0.12

Sift

Benign

0.66

T;T;T;T;.

Sift4G

Benign

0.62

T;T;T;T;T

Polyphen

0.0, 0.021

.;B;B;.;.

Vest4

0.26

MVP

0.73

ClinPred

0.038

GERP RS

4.7

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.091

gMVP

0.37

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

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over