20-2860506-G-A

Position:

chr20-2860506-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PP3_Moderate

The NM_022575.4(VPS16):c.427G>A(p.Gly143Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000118 in 1,613,812 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 12/21 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.000039 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000089 ( 0 hom. )

Consequence

VPS16
NM_022575.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2

Conservation

PhyloP100: 9.31

Variant links:

Genes affected

VPS16 (HGNC:14584): (VPS16 core subunit of CORVET and HOPS complexes) Vesicle mediated protein sorting plays an important role in segregation of intracellular molecules into distinct organelles. Genetic studies in yeast have identified more than 40 vacuolar protein sorting (VPS) genes involved in vesicle transport to vacuoles. This gene encodes the human homolog of yeast class C Vps16 protein. The mammalian class C Vps proteins are predominantly associated with late endosomes/lysosomes, and like their yeast counterparts, may mediate vesicle trafficking steps in the endosome/lysosome pathway. Two transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jul 2009]

VPS16 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.928

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
VPS16	NM_022575.4 linkuse as main transcript	c.427G>A	p.Gly143Arg	missense_variant	5/24	ENST00000380445.8
VPS16	NM_080413.3 linkuse as main transcript	c.427G>A	p.Gly143Arg	missense_variant	5/20

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
VPS16	ENST00000380445.8 linkuse as main transcript	c.427G>A	p.Gly143Arg	missense_variant	5/24	1	NM_022575.4	P1	Q9H269-1
VPS16	ENST00000380469.7 linkuse as main transcript	c.427G>A	p.Gly143Arg	missense_variant	5/20	2			Q9H269-2
VPS16	ENST00000453689.5 linkuse as main transcript	c.73G>A	p.Gly25Arg	missense_variant	3/10	3
VPS16	ENST00000417508.1 linkuse as main transcript	c.73G>A	p.Gly25Arg	missense_variant	3/9	5

Frequencies

GnomAD3 genomes

AF:

0.0000395

AC:

AN:

151992

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000725

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:

0.0000441

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00000795

AC:

AN:

251416

Hom.:

AF XY:

0.00000736

AC XY:

AN XY:

135894

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000176

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000889

AC:

AN:

1461820

Hom.:

Cov.:

AF XY:

0.00000688

AC XY:

AN XY:

727216

show subpopulations

Gnomad4 AFR exome

AF:

0.0000896

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000809

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000395

AC:

AN:

151992

Hom.:

Cov.:

AF XY:

0.0000404

AC XY:

AN XY:

74216

show subpopulations

Gnomad4 AFR

AF:

0.0000725

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:

0.0000441

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000540

Hom.:

Bravo

AF:

0.0000302

ExAC

AF:

0.00000824

AC:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

VPS16-related disorder

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jan 23, 2024

The VPS16 c.427G>A variant is predicted to result in the amino acid substitution p.Gly143Arg. To our knowledge, this variant has not been reported in the literature in association with VPS16-related dystonia. This variant was reported with de novo occurrence in an individual with an undefined developmental disorder (Turner et al 2019. PubMed ID: 31785789, supplemental table 2). However, it is also reported in 0.012% of alleles in individuals of African descent in gnomAD, calling the significance of the de novo occurrence in Turner et al. into question. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Inborn genetic diseases

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 12, 2021

The c.427G>A (p.G143R) alteration is located in exon 5 (coding exon 5) of the VPS16 gene. This alteration results from a G to A substitution at nucleotide position 427, causing the glycine (G) at amino acid position 143 to be replaced by an arginine (R). 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

Pathogenic

0.99

BayesDel_addAF

Pathogenic

0.36

BayesDel_noAF

Pathogenic

0.30

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.45

T;.;.;.

Eigen

Pathogenic

0.91

Eigen_PC

Pathogenic

0.83

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.94

D;D;D;D

M_CAP

Benign

0.063

MetaRNN

Pathogenic

0.93

D;D;D;D

MetaSVM

Uncertain

0.16

MutationAssessor

Pathogenic

3.2

M;M;.;.

MutationTaster

Benign

1.0

D;D

PrimateAI

Pathogenic

0.79

PROVEAN

Pathogenic

-7.6

D;D;D;D

REVEL

Pathogenic

0.72

Sift

Pathogenic

0.0

D;D;D;D

Sift4G

Uncertain

0.0020

D;D;D;D

Polyphen

1.0

D;D;.;.

Vest4

0.96

MutPred

0.94

Loss of sheet (P = 0.0315);Loss of sheet (P = 0.0315);.;.;

MVP

0.85

MPC

0.88

ClinPred

1.0

GERP RS

6.0

Varity_R

0.90

gMVP

0.96

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.040

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