Variant 13-52423614-G-A details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP3

The NM_016075.4(VPS36):c.800C>T(p.Thr267Met) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000192 in 1,610,456 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 Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000019 ( 0 hom. )

Consequence

VPS36
NM_016075.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 8.34

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]

VPS36 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.807

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
VPS36	NM_016075.4 linkuse as main transcript	c.800C>T	p.Thr267Met	missense_variant	10/14	ENST00000378060.9	NP_057159.2
VPS36	NM_001282168.2 linkuse as main transcript	c.773C>T	p.Thr258Met	missense_variant	10/14		NP_001269097.1
VPS36	NM_001282169.2 linkuse as main transcript	c.626C>T	p.Thr209Met	missense_variant	10/14		NP_001269098.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
VPS36	ENST00000378060.9 linkuse as main transcript	c.800C>T	p.Thr267Met	missense_variant	10/14	1	NM_016075.4	ENSP00000367299	P1	Q86VN1-1
VPS36	ENST00000611132.4 linkuse as main transcript	c.626C>T	p.Thr209Met	missense_variant	10/14	1		ENSP00000484968		Q86VN1-2
VPS36	ENST00000650274.1 linkuse as main transcript	c.800C>T	p.Thr267Met	missense_variant, NMD_transcript_variant	10/15			ENSP00000497484

Frequencies

GnomAD3 genomes

AF:

0.0000197

AC:

AN:

152098

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000385

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000320

AC:

AN:

249672

Hom.:

AF XY:

0.0000222

AC XY:

AN XY:

135036

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000293

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000617

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000192

AC:

AN:

1458358

Hom.:

Cov.:

AF XY:

0.0000207

AC XY:

AN XY:

725534

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.0000225

Gnomad4 ASJ exome

AF:

0.0000384

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000117

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000207

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

AF:

0.0000197

AC:

AN:

152098

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74294

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000385

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000227

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.0000330

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 30, 2021

The c.800C>T (p.T267M) alteration is located in exon 10 (coding exon 10) of the VPS36 gene. This alteration results from a C to T substitution at nucleotide position 800, causing the threonine (T) at amino acid position 267 to be replaced by a methionine (M). 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

Uncertain

0.35

BayesDel_addAF

Pathogenic

0.29

BayesDel_noAF

Pathogenic

0.36

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.24

.;T

Eigen

Pathogenic

0.78

Eigen_PC

Pathogenic

0.80

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Pathogenic

0.98

D;D

M_CAP

Benign

0.013

MetaRNN

Pathogenic

0.81

D;D

MetaSVM

Benign

-0.41

MutationAssessor

Benign

1.8

.;L

MutationTaster

Benign

1.0

PrimateAI

Uncertain

0.78

PROVEAN

Uncertain

-3.3

.;D

REVEL

Uncertain

0.34

Sift

Uncertain

0.0020

.;D

Sift4G

Uncertain

0.014

D;D

Polyphen

1.0

.;D

Vest4

0.82

MVP

0.44

MPC

1.4

ClinPred

0.84

GERP RS

5.9

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.58

gMVP

0.57

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

LitVar

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

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over