Variant 2-63916887-A-C details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_ModerateBP6_ModerateBS1BS2

The NM_016516.3(VPS54):c.2228+13T>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.021 in 1,612,604 control chromosomes in the GnomAD database, including 433 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

Frequency

Genomes: 𝑓 0.018 ( 31 hom., cov: 32)

Exomes 𝑓: 0.021 ( 402 hom. )

Consequence

VPS54
NM_016516.3 intron

Scores

Clinical Significance

Benign criteria provided, single submitter B:3

Conservation

PhyloP100: 0.934

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 Benign. Variant got -12 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.46).

BP6

Variant 2-63916887-A-C is Benign according to our data. Variant chr2-63916887-A-C is described in ClinVar as [Benign]. Clinvar id is 1209950.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr2-63916887-A-C is described in Lovd as [Likely_benign]. Variant chr2-63916887-A-C is described in Lovd as [Benign].

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0176 (2683/152210) while in subpopulation NFE AF= 0.0219 (1486/67936). AF 95% confidence interval is 0.0209. There are 31 homozygotes in gnomad4. There are 1434 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High AC in GnomAd4 at 2683 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
VPS54	NM_016516.3 linkuse as main transcript	c.2228+13T>G		intron_variant		ENST00000272322.9	NP_057600.2

Ensembl

Gene	Transcript	HGVSc	Effect	TSL	MANE	Protein	Appris	UniProt
VPS54	ENST00000272322.9 linkuse as main transcript	c.2228+13T>G	intron_variant	5	NM_016516.3	ENSP00000272322	P1	Q9P1Q0-1
VPS54	ENST00000354504.7 linkuse as main transcript	c.1769+13T>G	intron_variant	1		ENSP00000346499		Q9P1Q0-3
VPS54	ENST00000409558.8 linkuse as main transcript	c.2192+13T>G	intron_variant	1		ENSP00000386980		Q9P1Q0-4
VPS54	ENST00000416400.1 linkuse as main transcript	c.112+13T>G	intron_variant, NMD_transcript_variant	1		ENSP00000414725

Frequencies

GnomAD3 genomes

AF:

0.0176

AC:

2683

AN:

152092

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00384

Gnomad AMI

AF:

0.0406

Gnomad AMR

AF:

0.0120

Gnomad ASJ

AF:

0.0577

Gnomad EAS

AF:

0.000192

Gnomad SAS

AF:

0.00870

Gnomad FIN

AF:

0.0510

Gnomad MID

AF:

0.00633

Gnomad NFE

AF:

0.0219

Gnomad OTH

AF:

0.0149

GnomAD3 exomes

AF:

0.0194

AC:

4862

AN:

250686

Hom.:

AF XY:

0.0198

AC XY:

2684

AN XY:

135502

show subpopulations

Gnomad AFR exome

AF:

0.00320

Gnomad AMR exome

AF:

0.00745

Gnomad ASJ exome

AF:

0.0515

Gnomad EAS exome

AF:

0.0000545

Gnomad SAS exome

AF:

0.0103

Gnomad FIN exome

AF:

0.0463

Gnomad NFE exome

AF:

0.0229

Gnomad OTH exome

AF:

0.0204

GnomAD4 exome

AF:

0.0213

AC:

31168

AN:

1460394

Hom.:

402

Cov.:

AF XY:

0.0210

AC XY:

15252

AN XY:

726578

show subpopulations

Gnomad4 AFR exome

AF:

0.00308

Gnomad4 AMR exome

AF:

0.00765

Gnomad4 ASJ exome

AF:

0.0527

Gnomad4 EAS exome

AF:

0.000101

Gnomad4 SAS exome

AF:

0.0112

Gnomad4 FIN exome

AF:

0.0411

Gnomad4 NFE exome

AF:

0.0224

Gnomad4 OTH exome

AF:

0.0207

GnomAD4 genome

AF:

0.0176

AC:

2683

AN:

152210

Hom.:

Cov.:

AF XY:

0.0193

AC XY:

1434

AN XY:

74430

show subpopulations

Gnomad4 AFR

AF:

0.00382

Gnomad4 AMR

AF:

0.0120

Gnomad4 ASJ

AF:

0.0577

Gnomad4 EAS

AF:

0.000385

Gnomad4 SAS

AF:

0.00850

Gnomad4 FIN

AF:

0.0510

Gnomad4 NFE

AF:

0.0219

Gnomad4 OTH

AF:

0.0147

Alfa

AF:

0.0224

Hom.:

Bravo

AF:

0.0142

Asia WGS

AF:

0.00635

AC:

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -

not specified

Benign:1

Benign, no assertion criteria provided

clinical testing

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

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.46

CADD

Benign

7.6

DANN

Benign

0.80

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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