11-65096314-C-T

Variant names:

• chr11-65096314-C-T
• rs921803718
• NM_013265.4:c.64C>T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_013265.4(VPS51):​c.64C>T​(p.Pro22Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 7.4e-7 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: VPS51 NM_013265.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.0250
• 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: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.086671084).

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.64C>T	p.Pro22Ser	missense	Exon 1 of 10	NP_037397.2
	VPS51	NR_073519.2		n.101C>T		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.64C>T	p.Pro22Ser	missense	Exon 1 of 10	ENSP00000279281.3	Q9UID3-1
	VPS51	ENST00000940630.1		c.64C>T	p.Pro22Ser	missense	Exon 1 of 7	ENSP00000610689.1
	VPS51	ENST00000529180.1	TSL:3	c.64C>T	p.Pro22Ser	missense	Exon 1 of 4	ENSP00000435245.1	E9PKX7

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 7.38e-7 AC: 1 AN: 1355412 Hom.: 0 Cov.: 32 AF XY: 0.00000150 AC XY: 1 AN XY: 668580

African (AFR) AF: 0.00 AC: 0 AN: 28142

American (AMR) AF: 0.00 AC: 0 AN: 23036

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 22742

East Asian (EAS) AF: 0.00 AC: 0 AN: 33622

South Asian (SAS) AF: 0.0000134 AC: 1 AN: 74510

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 47920

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3916

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1065828

Other (OTH) AF: 0.00 AC: 0 AN: 55696

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.080
BayesDel_addAF	Benign	-0.24	T
BayesDel_noAF	Benign	-0.58
CADD	Benign	18
DANN	Uncertain	0.99
DEOGEN2	Benign	0.0052	T
Eigen	Benign	-0.81
Eigen_PC	Benign	-0.68
FATHMM_MKL	Benign	0.13	N
LIST_S2	Benign	0.70	T
M_CAP	Benign	0.0062	T
MetaRNN	Benign	0.087	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.97	L
PhyloP100		0.025
PrimateAI	Uncertain	0.68	T
PROVEAN	Benign	-0.040	N
REVEL	Benign	0.028
Sift	Benign	0.031	D
Sift4G	Benign	0.11	T
Polyphen		0.0020	B
Vest4		0.075
MutPred		0.20		Gain of phosphorylation at P22 (P = 0.0019)
MVP		0.092
MPC		0.70
ClinPred		0.13	T
GERP RS		3.4
PromoterAI		-0.016	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.6
Varity_R		0.044
gMVP		0.14
Mutation Taster		=93/7	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: rs921803718; hg19: chr11-64863786;