Variant chr2-63921237-C-T details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2PP3_Moderate

The NM_016516.3(VPS54):c.1838G>A(p.Arg613Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,456,996 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: 0.0000014 ( 0 hom. )

Consequence

VPS54
NM_016516.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 7.41

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:

VPS54 (HGNC:):

VPS54 links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 4 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.846

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
VPS54	NM_016516.3 linkuse as main transcript	c.1838G>A	p.Arg613Gln	missense_variant	13/23	ENST00000272322.9	NP_057600.2	Q9P1Q0-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
VPS54	ENST00000272322.9 linkuse as main transcript	c.1838G>A	p.Arg613Gln	missense_variant	13/23	5	NM_016516.3	ENSP00000272322.4	Q9P1Q0-1
VPS54	ENST00000409558.8 linkuse as main transcript	c.1802G>A	p.Arg601Gln	missense_variant	13/23	1		ENSP00000386980.3	Q9P1Q0-4
VPS54	ENST00000354504.7 linkuse as main transcript	c.1379G>A	p.Arg460Gln	missense_variant	10/20	1		ENSP00000346499.3	Q9P1Q0-3

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000137

AC:

AN:

1456996

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

724658

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:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000180

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

Alfa

AF:

0.0000370

Hom.:

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

Jul 12, 2022

The c.1838G>A (p.R613Q) alteration is located in exon 13 (coding exon 12) of the VPS54 gene. This alteration results from a G to A substitution at nucleotide position 1838, causing the arginine (R) at amino acid position 613 to be replaced by a glutamine (Q). 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

0.29

BayesDel_addAF

Pathogenic

0.26

BayesDel_noAF

Pathogenic

0.14

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.28

.;.;T

Eigen

Pathogenic

0.72

Eigen_PC

Pathogenic

0.68

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Pathogenic

0.99

D;D;D

M_CAP

Benign

0.052

MetaRNN

Pathogenic

0.85

D;D;D

MetaSVM

Benign

-0.64

MutationAssessor

Uncertain

2.7

.;.;M

MutationTaster

Benign

1.0

D;D;D;D

PrimateAI

Uncertain

0.51

PROVEAN

Benign

-2.3

N;N;N

REVEL

Uncertain

0.44

Sift

Benign

0.11

T;T;T

Sift4G

Benign

0.081

T;T;T

Polyphen

1.0

D;D;D

Vest4

0.97

MVP

0.48

MPC

0.20

ClinPred

1.0

GERP RS

4.7

Varity_R

0.34

gMVP

0.74

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