rs184277092

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 5P and 4B. PP2PP3_StrongBS2

The ENST00000299138.12(VPS35):​c.1570C>T​(p.Arg524Trp) variant causes a missense change. The variant allele was found at a frequency of 0.00000496 in 1,613,982 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as not provided (no stars).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)
Exomes 𝑓: 0.0000048 ( 0 hom. )

Consequence

VPS35
ENST00000299138.12 missense

Scores

13
5
1

Clinical Significance

not provided no classification provided O:1

Conservation

PhyloP100: 4.13
Variant links:
Genes affected
VPS35 (HGNC:13487): (VPS35 retromer complex component) This gene belongs to a group of vacuolar protein sorting (VPS) genes. The encoded protein is a component of a large multimeric complex, termed the retromer complex, involved in retrograde transport of proteins from endosomes to the trans-Golgi network. The close structural similarity between the yeast and human proteins that make up this complex suggests a similarity in function. Expression studies in yeast and mammalian cells indicate that this protein interacts directly with VPS35, which serves as the core of the retromer complex. [provided by RefSeq, Jul 2008]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 1 ACMG points.

PP2
Missense variant in gene, where missense usually causes diseases (based on misZ statistic), VPS35. . Gene score misZ 3.5321 (greater than the threshold 3.09). Trascript score misZ 4.8931 (greater than threshold 3.09). GenCC has associacion of gene with intellectual disability, hereditary late onset Parkinson disease, Parkinson disease, Parkinson disease 17.
PP3
MetaRNN computational evidence supports a deleterious effect, 0.963
BS2
High AC in GnomAdExome4 at 7 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
VPS35NM_018206.6 linkuse as main transcriptc.1570C>T p.Arg524Trp missense_variant 13/17 ENST00000299138.12 NP_060676.2
VPS35XM_011523227.4 linkuse as main transcriptc.1483C>T p.Arg495Trp missense_variant 13/17 XP_011521529.1
VPS35XM_005256045.4 linkuse as main transcriptc.1369C>T p.Arg457Trp missense_variant 11/15 XP_005256102.1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
VPS35ENST00000299138.12 linkuse as main transcriptc.1570C>T p.Arg524Trp missense_variant 13/171 NM_018206.6 ENSP00000299138 P1
VPS35ENST00000568784.6 linkuse as main transcriptc.*2240C>T 3_prime_UTR_variant, NMD_transcript_variant 13/171 ENSP00000456274
VPS35ENST00000562420.1 linkuse as main transcriptn.208C>T non_coding_transcript_exon_variant 1/42
VPS35ENST00000647959.1 linkuse as main transcriptc.*1633C>T 3_prime_UTR_variant, NMD_transcript_variant 14/18 ENSP00000497702

Frequencies

GnomAD3 genomes
AF:
0.00000657
AC:
1
AN:
152154
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.0000241
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.00
Gnomad OTH
AF:
0.00
GnomAD4 exome
AF:
0.00000479
AC:
7
AN:
1461828
Hom.:
0
Cov.:
31
AF XY:
0.00000688
AC XY:
5
AN XY:
727218
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.0000252
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00000540
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
AF:
0.00000657
AC:
1
AN:
152154
Hom.:
0
Cov.:
32
AF XY:
0.00
AC XY:
0
AN XY:
74328
show subpopulations
Gnomad4 AFR
AF:
0.0000241
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.00
Gnomad4 OTH
AF:
0.00

ClinVar

Significance: not provided
Submissions summary: Other:1
Revision: no classification provided
LINK: link

Submissions by phenotype

Parkinson disease 17 Other:1
not provided, no classification providedliterature onlyGeneReviews-- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.99
BayesDel_addAF
Pathogenic
0.33
D
BayesDel_noAF
Pathogenic
0.23
CADD
Pathogenic
32
DANN
Pathogenic
1.0
DEOGEN2
Uncertain
0.53
D
Eigen
Pathogenic
0.75
Eigen_PC
Uncertain
0.66
FATHMM_MKL
Pathogenic
0.97
D
LIST_S2
Uncertain
0.91
D
M_CAP
Uncertain
0.18
D
MetaRNN
Pathogenic
0.96
D
MetaSVM
Uncertain
0.036
D
MutationAssessor
Pathogenic
3.6
H
MutationTaster
Benign
1.0
D
PrimateAI
Pathogenic
0.95
D
PROVEAN
Pathogenic
-7.4
D
REVEL
Pathogenic
0.78
Sift
Pathogenic
0.0
D
Sift4G
Pathogenic
0.0
D
Polyphen
1.0
D
Vest4
0.95
MutPred
0.85
Loss of sheet (P = 0.0126);
MVP
0.68
MPC
1.4
ClinPred
1.0
D
GERP RS
4.6
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.1
Varity_R
0.87
gMVP
0.84

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.040
Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs184277092; hg19: chr16-46702919; API