Variant 2-63914195-G-A details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_016516.3(VPS54):c.2321C>T(p.Ser774Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000274 in 1,460,312 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000027 ( 0 hom. )

Consequence

VPS54
NM_016516.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 10.0

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:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
VPS54	NM_016516.3 linkuse as main transcript	c.2321C>T	p.Ser774Leu	missense_variant	17/23	ENST00000272322.9	NP_057600.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
VPS54	ENST00000272322.9 linkuse as main transcript	c.2321C>T	p.Ser774Leu	missense_variant	17/23	5	NM_016516.3	ENSP00000272322	P1	Q9P1Q0-1
VPS54	ENST00000409558.8 linkuse as main transcript	c.2285C>T	p.Ser762Leu	missense_variant	17/23	1		ENSP00000386980		Q9P1Q0-4
VPS54	ENST00000354504.7 linkuse as main transcript	c.1862C>T	p.Ser621Leu	missense_variant	14/20	1		ENSP00000346499		Q9P1Q0-3
VPS54	ENST00000416400.1 linkuse as main transcript	c.206C>T	p.Ser69Leu	missense_variant, NMD_transcript_variant	3/10	1		ENSP00000414725

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000274

AC:

AN:

1460312

Hom.:

Cov.:

AF XY:

0.00000551

AC XY:

AN XY:

726440

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:

0.00000360

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

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 30, 2024

The c.2321C>T (p.S774L) alteration is located in exon 17 (coding exon 16) of the VPS54 gene. This alteration results from a C to T substitution at nucleotide position 2321, causing the serine (S) at amino acid position 774 to be replaced by a leucine (L). 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

0.19

BayesDel_addAF

Uncertain

0.017

BayesDel_noAF

Benign

-0.21

CADD

Uncertain

DANN

Benign

0.87

DEOGEN2

Benign

0.053

.;.;T

Eigen

Benign

-0.16

Eigen_PC

Benign

0.16

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Pathogenic

0.99

D;D;D

M_CAP

Benign

0.019

MetaRNN

Uncertain

0.45

T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

-1.0

.;.;N

MutationTaster

Benign

1.0

D;D;D;D

PrimateAI

Uncertain

0.77

PROVEAN

Benign

-0.070

N;N;N

REVEL

Benign

0.29

Sift

Benign

0.45

T;T;T

Sift4G

Benign

0.60

T;T;T

Polyphen

0.0080

B;B;B

Vest4

0.64

MutPred

0.61

.;.;Gain of ubiquitination at K778 (P = 0.0856);

MVP

0.17

MPC

0.60

ClinPred

0.89

GERP RS

6.0

Varity_R

0.098

gMVP

0.72

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

No publications associated with this variant yet.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over