13-52423602-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2PP3_Moderate

The NM_016075.4(VPS36):​c.812G>A​(p.Cys271Tyr) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Consequence

VPS36
NM_016075.4 missense

Scores

11
6
2

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 6.59
Variant links:
Genes affected
VPS36 (HGNC:20312): (vacuolar protein sorting 36 homolog) This gene encodes a protein that is a subunit of the endosomal sorting complex required for transport II (ESCRT-II). This protein complex functions in sorting of ubiquitinated membrane proteins during endocytosis. A similar protein complex in rat is associated with RNA polymerase elongation factor II. [provided by RefSeq, Aug 2013]

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 4 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.92

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
VPS36NM_016075.4 linkc.812G>A p.Cys271Tyr missense_variant Exon 10 of 14 ENST00000378060.9 NP_057159.2 Q86VN1-1
VPS36NM_001282168.2 linkc.785G>A p.Cys262Tyr missense_variant Exon 10 of 14 NP_001269097.1
VPS36NM_001282169.2 linkc.638G>A p.Cys213Tyr missense_variant Exon 10 of 14 NP_001269098.1 Q86VN1-2

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
VPS36ENST00000378060.9 linkc.812G>A p.Cys271Tyr missense_variant Exon 10 of 14 1 NM_016075.4 ENSP00000367299.3 Q86VN1-1
VPS36ENST00000611132.4 linkc.638G>A p.Cys213Tyr missense_variant Exon 10 of 14 1 ENSP00000484968.1 Q86VN1-2
VPS36ENST00000650274.1 linkn.812G>A non_coding_transcript_exon_variant Exon 10 of 15 ENSP00000497484.1 A0A3B3ISW7

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
Cov.:
29
GnomAD4 genome
Cov.:
32

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not specified Uncertain:1
Dec 02, 2024
Ambry Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The c.812G>A (p.C271Y) alteration is located in exon 10 (coding exon 10) of the VPS36 gene. This alteration results from a G to A substitution at nucleotide position 812, causing the cysteine (C) at amino acid position 271 to be replaced by a tyrosine (Y). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.99
BayesDel_addAF
Pathogenic
0.47
D
BayesDel_noAF
Pathogenic
0.43
CADD
Pathogenic
29
DANN
Uncertain
1.0
DEOGEN2
Uncertain
0.48
.;T
Eigen
Pathogenic
0.91
Eigen_PC
Pathogenic
0.88
FATHMM_MKL
Pathogenic
0.99
D
LIST_S2
Pathogenic
0.98
D;D
M_CAP
Benign
0.031
D
MetaRNN
Pathogenic
0.92
D;D
MetaSVM
Uncertain
0.079
D
MutationAssessor
Uncertain
2.6
.;M
PrimateAI
Pathogenic
0.88
D
PROVEAN
Pathogenic
-9.5
.;D
REVEL
Uncertain
0.48
Sift
Pathogenic
0.0
.;D
Sift4G
Uncertain
0.0020
D;D
Polyphen
1.0
.;D
Vest4
0.94
MutPred
0.76
.;Gain of catalytic residue at C271 (P = 0.0288);
MVP
0.72
MPC
1.8
ClinPred
1.0
D
GERP RS
5.9
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7
Varity_R
0.98
gMVP
0.88

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.010
Details are displayed if max score is > 0.2

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr13-52997737; API