Variant 3-184834696-G-A details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP3

The NM_001009921.3(VPS8):c.401G>A(p.Arg134His) variant causes a missense change. The variant allele was found at a frequency of 0.00000283 in 1,411,384 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000028 ( 0 hom. )

Consequence

VPS8
NM_001009921.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 6.89

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:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.778

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
VPS8	NM_001009921.3 linkuse as main transcript	c.401G>A	p.Arg134His	missense_variant	5/48	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.401G>A	p.Arg134His	missense_variant	5/48	5	NM_001009921.3	ENSP00000487164	A1	Q8N3P4-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000283

AC:

AN:

1411384

Hom.:

Cov.:

AF XY:

0.00000430

AC XY:

AN XY:

697132

show subpopulations

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:

0.0000125

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000277

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

Alfa

AF:

0.0000282

Hom.:

Bravo

AF:

0.00000756

ExAC

AF:

0.0000170

AC:

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

May 29, 2024

The c.401G>A (p.R134H) alteration is located in exon 5 (coding exon 4) of the VPS8 gene. This alteration results from a G to A substitution at nucleotide position 401, causing the arginine (R) at amino acid position 134 to be replaced by a histidine (H). 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

0.11

BayesDel_addAF

Benign

-0.000020

BayesDel_noAF

Benign

-0.24

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.24

.;.;.;T;T;T;.

Eigen

Uncertain

0.53

Eigen_PC

Uncertain

0.57

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Uncertain

0.96

D;D;D;D;D;D;D

M_CAP

Benign

0.013

MetaRNN

Pathogenic

0.78

D;D;D;D;D;D;D

MetaSVM

Benign

-0.50

MutationAssessor

Benign

1.5

.;L;L;.;L;.;.

MutationTaster

Benign

1.0

D;D;D;D;N

PrimateAI

Uncertain

0.76

PROVEAN

Uncertain

-2.5

D;D;D;D;.;D;D

REVEL

Benign

0.20

Sift

Benign

0.035

D;D;D;D;.;T;D

Sift4G

Uncertain

0.0080

D;D;D;D;D;D;D

Polyphen

1.0, 0.059

.;D;B;.;.;.;D

Vest4

0.44

MutPred

0.78

Gain of glycosylation at S131 (P = 0.0181);Gain of glycosylation at S131 (P = 0.0181);Gain of glycosylation at S131 (P = 0.0181);Gain of glycosylation at S131 (P = 0.0181);Gain of glycosylation at S131 (P = 0.0181);Gain of glycosylation at S131 (P = 0.0181);Gain of glycosylation at S131 (P = 0.0181);

MVP

0.72

ClinPred

0.85

GERP RS

5.1

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.12

gMVP

0.76

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