9-77219986-G-T

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_033305.3(VPS13A):c.787G>T(p.Val263Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000658 in 151,870 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V263M) has been classified as Uncertain significance.

Frequency

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

Consequence

VPS13A
NM_033305.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.71

Publications

0 publications found

Variant links:

Genes affected

VPS13A (HGNC:1908): (vacuolar protein sorting 13 homolog A) The protein encoded by this gene may control steps in the cycling of proteins through the trans-Golgi network to endosomes, lysosomes and the plasma membrane. Mutations in this gene cause the autosomal recessive disorder, chorea-acanthocytosis. Alternative splicing of this gene results in multiple transcript variants. [provided by RefSeq, Jul 2008]

VPS13A Gene-Disease associations (from GenCC):

chorea-acanthocytosis
Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, Genomics England PanelApp, Ambry Genetics, Labcorp Genetics (formerly Invitae)

VPS13A links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.060874164).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
VPS13A	NM_033305.3 link	c.787G>T	p.Val263Leu	missense_variant	Exon 11 of 72	ENST00000360280.8	NP_150648.2	Q96RL7-1
VPS13A	NM_001018037.2 link	c.787G>T	p.Val263Leu	missense_variant	Exon 11 of 71		NP_001018047.1	Q96RL7-3
VPS13A	NM_015186.4 link	c.787G>T	p.Val263Leu	missense_variant	Exon 11 of 69		NP_056001.1	Q96RL7-2
VPS13A	NM_001018038.3 link	c.787G>T	p.Val263Leu	missense_variant	Exon 11 of 69		NP_001018048.1	Q96RL7-4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
VPS13A	ENST00000360280.8 link	c.787G>T	p.Val263Leu	missense_variant	Exon 11 of 72	1	NM_033305.3	ENSP00000353422.3	Q96RL7-1
VPS13A	ENST00000376636.7 link	c.787G>T	p.Val263Leu	missense_variant	Exon 11 of 71	1		ENSP00000365823.3	Q96RL7-3
VPS13A	ENST00000643348.1 link	c.787G>T	p.Val263Leu	missense_variant	Exon 11 of 69			ENSP00000493592.1	Q96RL7-2
VPS13A	ENST00000645632.1 link	c.787G>T	p.Val263Leu	missense_variant	Exon 11 of 69			ENSP00000496361.1	Q96RL7-4

Frequencies

GnomAD3 genomes

AF:

0.00000658

AC:

AN:

151870

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000242

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

Cov.:

GnomAD4 genome

AF:

0.00000658

AC:

AN:

151870

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74132

show subpopulations

African (AFR)

AF:

0.0000242

AC:

AN:

41332

American (AMR)

AF:

0.00

AC:

AN:

15242

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5180

South Asian (SAS)

AF:

0.00

AC:

AN:

4812

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10548

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

67978

Other (OTH)

AF:

0.00

AC:

AN:

2082

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Uncertain:1

May 20, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is not present in population databases (gnomAD no frequency). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. This variant has not been reported in the literature in individuals affected with VPS13A-related conditions. This sequence change replaces valine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 263 of the VPS13A protein (p.Val263Leu). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.090

BayesDel_addAF

Benign

-0.29

BayesDel_noAF

Benign

-0.66

CADD

Benign

(source)

DANN

Benign

0.94

DEOGEN2

Benign

0.076

.;.;T;.;.;.;T

Eigen

Benign

-0.75

Eigen_PC

Benign

-0.55

FATHMM_MKL

Uncertain

0.78

LIST_S2

Benign

0.81

.;T;.;.;T;T;T

M_CAP

Benign

0.0062

MetaRNN

Benign

0.061

T;T;T;T;T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

-0.69

N;N;N;N;N;N;N

PhyloP100

1.7

PrimateAI

Benign

0.24

PROVEAN

Benign

0.18

N;N;N;N;.;.;.

REVEL

Benign

0.039

Sift

Benign

0.14

T;T;T;T;.;.;.

Sift4G

Benign

0.64

T;T;T;T;.;.;.

Polyphen

0.0

B;B;B;B;B;B;B

Vest4

0.21

MutPred

0.29

Loss of sheet (P = 0.0817);Loss of sheet (P = 0.0817);Loss of sheet (P = 0.0817);Loss of sheet (P = 0.0817);Loss of sheet (P = 0.0817);Loss of sheet (P = 0.0817);Loss of sheet (P = 0.0817);

MVP

0.25

MPC

0.13

ClinPred

0.090

GERP RS

1.1

Varity_R

0.057

gMVP

0.42

Mutation Taster

=89/11

polymorphism

(source)

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over