chr11-65107689-C-T

Variant names:

• chr11-65107689-C-T
• rs1422535406
• NM_013265.4:c.467C>T

Variant summary

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

The NM_013265.4(VPS51):​c.467C>T​(p.Thr156Met) variant causes a missense change. The variant allele was found at a frequency of 0.00000206 in 1,457,604 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: VPS51 NM_013265.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.47
• 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)

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_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.467C>T	p.Thr156Met	missense	Exon 3 of 10	NP_037397.2
	VPS51	NR_073519.2		n.504C>T		non_coding_transcript_exon	Exon 3 of 10

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	VPS51	ENST00000279281.8	TSL:1 MANE Select	c.467C>T	p.Thr156Met	missense	Exon 3 of 10	ENSP00000279281.3	Q9UID3-1
	VPS51	ENST00000527646.5	TSL:1	n.142C>T		non_coding_transcript_exon	Exon 2 of 9
	VPS51	ENST00000529180.1	TSL:3	c.467C>T	p.Thr156Met	missense	Exon 3 of 4	ENSP00000435245.1	E9PKX7

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.00000403 AC: 1 AN: 247964 AF XY: 0.00

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: 0.0000480

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000206 AC: 3 AN: 1457604 Hom.: 0 Cov.: 32 AF XY: 0.00000276 AC XY: 2 AN XY: 724432

African (AFR) AF: 0.00 AC: 0 AN: 33434

American (AMR) AF: 0.00 AC: 0 AN: 44642

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26098

East Asian (EAS) AF: 0.00 AC: 0 AN: 39568

South Asian (SAS) AF: 0.00 AC: 0 AN: 86184

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52190

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5764

European-Non Finnish (NFE) AF: 0.00000180 AC: 2 AN: 1109506

Other (OTH) AF: 0.0000166 AC: 1 AN: 60218

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000756

EpiCase AF: 0.0000545

EpiControl AF: 0.00

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	Uncertain	0.48
BayesDel_addAF	Pathogenic	0.17	D
BayesDel_noAF	Uncertain	0.010
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.54	D
Eigen	Uncertain	0.62
Eigen_PC	Uncertain	0.55
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.94	D
M_CAP	Benign	0.036	D
MetaRNN	Uncertain	0.58	D
MetaSVM	Uncertain	-0.13	T
MutationAssessor	Uncertain	2.6	M
PhyloP100		4.5
PrimateAI	Uncertain	0.62	T
PROVEAN	Uncertain	-3.7	D
REVEL	Benign	0.25
Sift	Uncertain	0.0010	D
Sift4G	Pathogenic	0.0010	D
Polyphen		1.0	D
Vest4		0.58
MutPred		0.36		Gain of MoRF binding (P = 0.1131)
MVP		0.43
MPC		1.6
ClinPred		0.98	D
GERP RS		4.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.41
gMVP		0.61
Mutation Taster		=60/40	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: rs1422535406; hg19: chr11-64875161;