chr2-63920551-G-C

Variant names:

• chr2-63920551-G-C
• rs1200103911
• NM_016516.3:c.1946C>G

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_016516.3(VPS54):​c.1946C>G​(p.Thr649Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000281 in 1,425,684 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: 0.0000028 (0 hom.)
• Consequence: VPS54 NM_016516.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 9.68
• Publications: 0 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: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

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.1946C>G	p.Thr649Ser	missense	Exon 14 of 23	NP_057600.2	Q9P1Q0-1
	VPS54	NM_001005739.2		c.1910C>G	p.Thr637Ser	missense	Exon 14 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.1946C>G	p.Thr649Ser	missense	Exon 14 of 23	ENSP00000272322.4	Q9P1Q0-1
	VPS54	ENST00000409558.8	TSL:1	c.1910C>G	p.Thr637Ser	missense	Exon 14 of 23	ENSP00000386980.3	Q9P1Q0-4
	VPS54	ENST00000354504.7	TSL:1	c.1487C>G	p.Thr496Ser	missense	Exon 11 of 20	ENSP00000346499.3	Q9P1Q0-3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000445 AC: 1 AN: 224694 AF XY: 0.00000813

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000971

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000281 AC: 4 AN: 1425684 Hom.: 0 Cov.: 30 AF XY: 0.00000423 AC XY: 3 AN XY: 709560

African (AFR) AF: 0.00 AC: 0 AN: 30956

American (AMR) AF: 0.00 AC: 0 AN: 40404

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25166

East Asian (EAS) AF: 0.00 AC: 0 AN: 36674

South Asian (SAS) AF: 0.00 AC: 0 AN: 81654

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52314

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5654

European-Non Finnish (NFE) AF: 0.00000366 AC: 4 AN: 1094342

Other (OTH) AF: 0.00 AC: 0 AN: 58520

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.21
BayesDel_addAF	Uncertain	0.096	D
BayesDel_noAF	Benign	-0.10
CADD	Benign	23
DANN	Uncertain	0.99
DEOGEN2	Benign	0.12	T
Eigen	Uncertain	0.55
Eigen_PC	Uncertain	0.62
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.85	T
M_CAP	Benign	0.012	T
MetaRNN	Uncertain	0.49	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.1	M
PhyloP100		9.7
PrimateAI	Uncertain	0.67	T
PROVEAN	Benign	-0.56	N
REVEL	Benign	0.21
Sift	Benign	0.28	T
Sift4G	Benign	0.70	T
Polyphen		0.74	P
Vest4		0.57
MutPred		0.70		Loss of helix (P = 0.079)
MVP		0.25
MPC		0.045
ClinPred		0.62	D
GERP RS		5.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.16
gMVP		0.31
Mutation Taster		=44/56	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.12		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: rs1200103911; hg19: chr2-64147685;