2-63897588-C-A

Position:

• chr2-63897588-C-A

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

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 same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.15 (1771 hom., cov: 33)
  • Exomes 𝑓: 0.15 (15502 hom.)
• Consequence: VPS54 NM_016516.3 missense, splice_region
• Clinical Significance: Benign criteria provided, single submitter B:3
• Conservation: PhyloP100: 3.24

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]

ACMG classification

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/exons	MANE	Protein	UniProt
VPS54	NM_016516.3	c.2736G>T	p.Met912Ile	missense_variant, splice_region_variant	22/23	ENST00000272322.9	NP_057600.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
VPS54	ENST00000272322.9	c.2736G>T	p.Met912Ile	missense_variant, splice_region_variant	22/23	5	NM_016516.3	ENSP00000272322.4

Frequencies

GnomAD3 genomes AF: 0.149 AC: 22676 AN: 151952 Hom.: 1771 Cov.: 33

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

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.: 21 AF XY: 0.149 AC XY: 101164 AN XY: 678408

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.: 33 AF XY: 0.148 AC XY: 11030 AN XY: 74344

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

Submissions by phenotype

not specified Benign:2

Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -

not provided Benign:1

Benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

-

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.34
BayesDel_addAF	Benign	-0.55	T
BayesDel_noAF	Benign	-0.41
CADD	Benign	20
DANN	Benign	0.97
DEOGEN2	Benign	0.089	.;.;T
Eigen	Benign	-0.058
Eigen_PC	Benign	0.13
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.89	D;D;D
MetaRNN	Benign	0.0017	T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.6	.;.;L
MutationTaster	Benign	0.00019	P;P;P;P
PrimateAI	Uncertain	0.74	T
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	T
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

Other links and lift over

dbSNP: rs11558741; hg19: chr2-64124722; COSMIC: COSV55446239;