11-65096282-C-G

Variant names:

• chr11-65096282-C-G
• rs747134833
• NM_013265.4:c.32C>G

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_013265.4(VPS51):​c.32C>G​(p.Pro11Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000731 in 1,367,194 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P11L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 7.3e-7 (0 hom.)
• Consequence: VPS51 NM_013265.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.00600
• Publications: 0 publications found

Genes affected

VPS51 (HGNC:1172): (VPS51 subunit of GARP complex) This gene encodes a member of the vacuolar protein sorting-associated protein 51 family. The encoded protein is a component of the Golgi-associated retrograde protein complex which acts as a tethering factor for carriers in retrograde transport from the early and late endosomes to the trans-Golgi network. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Dec 2012]

VPS51 Gene-Disease associations (from GenCC):

• pontocerebellar hypoplasia, type 13

  Inheritance: AR, Unknown Classification: LIMITED Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)

ENSG00000303595 (HGNC:):

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.055368006).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_013265.4. 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
	VPS51	NM_013265.4	MANE Select	c.32C>G	p.Pro11Arg	missense	Exon 1 of 10	NP_037397.2
	VPS51	NR_073519.2		n.69C>G		non_coding_transcript_exon	Exon 1 of 10

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	VPS51	ENST00000279281.8	TSL:1 MANE Select	c.32C>G	p.Pro11Arg	missense	Exon 1 of 10	ENSP00000279281.3	Q9UID3-1
	VPS51	ENST00000940630.1		c.32C>G	p.Pro11Arg	missense	Exon 1 of 7	ENSP00000610689.1
	VPS51	ENST00000529180.1	TSL:3	c.32C>G	p.Pro11Arg	missense	Exon 1 of 4	ENSP00000435245.1	E9PKX7

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 7.31e-7 AC: 1 AN: 1367194 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 675426

African (AFR) AF: 0.00 AC: 0 AN: 28602

American (AMR) AF: 0.00 AC: 0 AN: 28238

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24014

East Asian (EAS) AF: 0.00 AC: 0 AN: 32688

South Asian (SAS) AF: 0.00 AC: 0 AN: 76334

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 46996

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4032

European-Non Finnish (NFE) AF: 9.35e-7 AC: 1 AN: 1069794

Other (OTH) AF: 0.00 AC: 0 AN: 56496

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.087
BayesDel_addAF	Benign	-0.19	T
BayesDel_noAF	Benign	-0.51
CADD	Benign	5.3
DANN	Benign	0.61
DEOGEN2	Benign	0.0073	T
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.057	N
LIST_S2	Benign	0.70	T
M_CAP	Benign	0.0063	T
MetaRNN	Benign	0.055	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.90	L
PhyloP100		0.0060
PrimateAI	Uncertain	0.70	T
PROVEAN	Benign	-0.24	N
REVEL	Benign	0.021
Sift	Benign	0.065	T
Sift4G	Benign	0.080	T
Polyphen		0.0	B
Vest4		0.15
MutPred		0.20		Gain of methylation at P11 (P = 0.0078)
MVP		0.10
MPC		0.73
ClinPred		0.13	T
GERP RS		1.1
PromoterAI		0.011	Neutral
Varity_R		0.028
gMVP		0.22
Mutation Taster		=98/2	polymorphism

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

Other links and lift over

dbSNP: rs747134833; hg19: chr11-64863754;