chr2-63897588-C-A

Variant names:

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_StrongBP6_ModerateBA1

The NM_016516.3(VPS54):c.2736G>T(p.Met912Ile) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.148 in 1,508,558 control chromosomes in the GnomAD database, including 17,273 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in UniProt.

Frequency

Genomes: 𝑓 0.15 ( 1771 hom., cov: 33)

Exomes 𝑓: 0.15 ( 15502 hom. )

Consequence

VPS54
NM_016516.3 missense, splice_region

Scores

Clinical Significance

Benign criteria provided, single submitter B:3

Conservation

PhyloP100: 3.24

Variant links:

Genes affected

VPS54 (HGNC:18652): (VPS54 subunit of GARP complex) This gene encodes for a protein that in yeast forms part of a trimeric vacuolar-protein-sorting complex that is required for retrograde transport of proteins from prevacuoles to the late Golgi compartment. As in yeast, mammalian Vps54 proteins contain a coiled-coil region and dileucine motifs. Alternative splicing results in multiple transcript variants encoding different isoforms [provided by RefSeq, Jul 2008]

VPS54 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -14 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0017487705).

BP6

Variant 2-63897588-C-A is Benign according to our data. Variant chr2-63897588-C-A is described in ClinVar as [Benign]. Clinvar id is 1210060.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr2-63897588-C-A is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.154 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
VPS54	NM_016516.3 link	c.2736G>T	p.Met912Ile	missense_variant, splice_region_variant	Exon 22 of 23	ENST00000272322.9	NP_057600.2	Q9P1Q0-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
VPS54	ENST00000272322.9 link	c.2736G>T	p.Met912Ile	missense_variant, splice_region_variant	Exon 22 of 23	5	NM_016516.3	ENSP00000272322.4		Q9P1Q0-1

Frequencies

GnomAD3 genomes

AF:

0.149

AC:

22676

AN:

151952

Hom.:

1771

Cov.:

show subpopulations

Gnomad AFR

AF:

0.154

Gnomad AMI

AF:

0.0758

Gnomad AMR

AF:

0.145

Gnomad ASJ

AF:

0.169

Gnomad EAS

AF:

0.0856

Gnomad SAS

AF:

0.153

Gnomad FIN

AF:

0.115

Gnomad MID

AF:

0.203

Gnomad NFE

AF:

0.157

Gnomad OTH

AF:

0.154

GnomAD3 exomes

AF:

0.144

AC:

32795

AN:

227766

Hom.:

2477

AF XY:

0.146

AC XY:

18017

AN XY:

123506

show subpopulations

Gnomad AFR exome

AF:

0.157

Gnomad AMR exome

AF:

0.135

Gnomad ASJ exome

AF:

0.186

Gnomad EAS exome

AF:

0.0834

Gnomad SAS exome

AF:

0.153

Gnomad FIN exome

AF:

0.111

Gnomad NFE exome

AF:

0.154

Gnomad OTH exome

AF:

0.161

GnomAD4 exome

AF:

0.148

AC:

200640

AN:

1356488

Hom.:

15502

Cov.:

AF XY:

0.149

AC XY:

101164

AN XY:

678408

show subpopulations

Gnomad4 AFR exome

AF:

0.153

Gnomad4 AMR exome

AF:

0.138

Gnomad4 ASJ exome

AF:

0.185

Gnomad4 EAS exome

AF:

0.0714

Gnomad4 SAS exome

AF:

0.154

Gnomad4 FIN exome

AF:

0.109

Gnomad4 NFE exome

AF:

0.151

Gnomad4 OTH exome

AF:

0.147

GnomAD4 genome

AF:

0.149

AC:

22681

AN:

152070

Hom.:

1771

Cov.:

AF XY:

0.148

AC XY:

11030

AN XY:

74344

show subpopulations

Gnomad4 AFR

AF:

0.154

Gnomad4 AMR

AF:

0.145

Gnomad4 ASJ

AF:

0.169

Gnomad4 EAS

AF:

0.0847

Gnomad4 SAS

AF:

0.154

Gnomad4 FIN

AF:

0.115

Gnomad4 NFE

AF:

0.157

Gnomad4 OTH

AF:

0.152

Alfa

AF:

0.157

Hom.:

3020

Bravo

AF:

0.151

TwinsUK

AF:

0.156

AC:

579

ALSPAC

AF:

0.142

AC:

546

ESP6500AA

AF:

0.137

AC:

600

ESP6500EA

AF:

0.150

AC:

1292

ExAC

AF:

0.144

AC:

17482

Asia WGS

AF:

0.0940

AC:

325

AN:

3466

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Benign:2

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Genome Diagnostics Laboratory, Amsterdam University Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

not provided

Benign:1

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.34

BayesDel_addAF

Benign

-0.55

BayesDel_noAF

Benign

-0.41

CADD

Benign

DANN

Benign

0.97

DEOGEN2

Benign

0.089

.;.;T

Eigen

Benign

-0.058

Eigen_PC

Benign

0.13

FATHMM_MKL

Uncertain

0.95

LIST_S2

Uncertain

0.89

D;D;D

MetaRNN

Benign

0.0017

T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.6

.;.;L

PrimateAI

Uncertain

0.74

PROVEAN

Benign

-0.62

N;N;N

REVEL

Benign

0.083

Sift

Benign

0.19

T;T;T

Sift4G

Benign

0.19

T;T;T

Polyphen

0.0

B;B;B

Vest4

0.15

MutPred

0.28

.;.;Loss of MoRF binding (P = 0.264);

MPC

0.72

ClinPred

0.015

GERP RS

4.7

Varity_R

0.18

gMVP

0.54

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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