rs11558741

Variant names:

• chr2-63897588-C-A
• rs11558741
• NM_016516.3:c.2736G>T

Variant summary

Our verdict is Benign. The variant received -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. 14/21 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 (★).

• 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
• Publications: 17 publications found

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

Our verdict: Benign. The variant received -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 VariationId is 1210060.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.154 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_016516.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	VPS54	NM_016516.3	MANE Select	c.2736G>T	p.Met912Ile	missense splice_region	Exon 22 of 23	NP_057600.2	Q9P1Q0-1
	VPS54	NM_001005739.2		c.2700G>T	p.Met900Ile	missense splice_region	Exon 22 of 23	NP_001005739.1	Q9P1Q0-4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	VPS54	ENST00000272322.9	TSL:5 MANE Select	c.2736G>T	p.Met912Ile	missense splice_region	Exon 22 of 23	ENSP00000272322.4	Q9P1Q0-1
	VPS54	ENST00000409558.8	TSL:1	c.2700G>T	p.Met900Ile	missense splice_region	Exon 22 of 23	ENSP00000386980.3	Q9P1Q0-4
	VPS54	ENST00000354504.7	TSL:1	c.2277G>T	p.Met759Ile	missense splice_region	Exon 19 of 20	ENSP00000346499.3	Q9P1Q0-3

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

GnomAD2 exomes AF: 0.144 AC: 32795 AN: 227766 AF XY: 0.146

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 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

African (AFR) AF: 0.153 AC: 4686 AN: 30540

American (AMR) AF: 0.138 AC: 5443 AN: 39564

Ashkenazi Jewish (ASJ) AF: 0.185 AC: 4630 AN: 25020

East Asian (EAS) AF: 0.0714 AC: 2761 AN: 38676

South Asian (SAS) AF: 0.154 AC: 12092 AN: 78426

European-Finnish (FIN) AF: 0.109 AC: 5574 AN: 51112

Middle Eastern (MID) AF: 0.228 AC: 1249 AN: 5470

European-Non Finnish (NFE) AF: 0.151 AC: 155865 AN: 1030932

Other (OTH) AF: 0.147 AC: 8340 AN: 56748

GnomAD4 genome AF: 0.149 AC: 22681 AN: 152070 Hom.: 1771 Cov.: 33 AF XY: 0.148 AC XY: 11030 AN XY: 74344

African (AFR) AF: 0.154 AC: 6401 AN: 41492

American (AMR) AF: 0.145 AC: 2211 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.169 AC: 588 AN: 3470

East Asian (EAS) AF: 0.0847 AC: 439 AN: 5186

South Asian (SAS) AF: 0.154 AC: 743 AN: 4822

European-Finnish (FIN) AF: 0.115 AC: 1210 AN: 10548

Middle Eastern (MID) AF: 0.201 AC: 59 AN: 294

European-Non Finnish (NFE) AF: 0.157 AC: 10639 AN: 67956

Other (OTH) AF: 0.152 AC: 322 AN: 2116

Alfa AF: 0.156 Hom.: 4748

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

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	2	not specified (2)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

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
MetaRNN	Benign	0.0017	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.6	L
PhyloP100		3.2
PrimateAI	Uncertain	0.74	T
PROVEAN	Benign	-0.62	N
REVEL	Benign	0.083
Sift	Benign	0.19	T
Sift4G	Benign	0.19	T
Polyphen		0.0	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
Mutation Taster		=96/4	polymorphism (auto)

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

Other links and lift over

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