rs202090510

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The NM_033305.3(VPS13A):c.398C>T(p.Pro133Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00022 in 1,610,904 control chromosomes in the GnomAD database, including 1 homozygotes. 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 (★★). Synonymous variant affecting the same amino acid position (i.e. P133P) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.00011 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00023 ( 1 hom. )

Consequence

VPS13A
NM_033305.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:3

Conservation

PhyloP100: 0.394

Publications

3 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 -4 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.013561219).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein
VPS13A	NM_033305.3 link	c.398C>T	p.Pro133Leu	missense_variant	Exon 6 of 72	ENST00000360280.8	NP_150648.2
VPS13A	NM_001018037.2 link	c.398C>T	p.Pro133Leu	missense_variant	Exon 6 of 71		NP_001018047.1
VPS13A	NM_015186.4 link	c.398C>T	p.Pro133Leu	missense_variant	Exon 6 of 69		NP_056001.1
VPS13A	NM_001018038.3 link	c.398C>T	p.Pro133Leu	missense_variant	Exon 6 of 69		NP_001018048.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
VPS13A	ENST00000360280.8 link	c.398C>T	p.Pro133Leu	missense_variant	Exon 6 of 72	1	NM_033305.3	ENSP00000353422.3

Frequencies

GnomAD3 genomes

AF:

0.000105

AC:

AN:

151834

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000242

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000263

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:

0.000162

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000276

AC:

AN:

249580

AF XY:

0.000244

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000871

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000546

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000186

Gnomad OTH exome

AF:

0.000494

GnomAD4 exome

AF:

0.000232

AC:

339

AN:

1458952

Hom.:

Cov.:

AF XY:

0.000207

AC XY:

150

AN XY:

725804

show subpopulations

African (AFR)

AF:

0.000180

AC:

AN:

33412

American (AMR)

AF:

0.000784

AC:

AN:

44668

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26068

East Asian (EAS)

AF:

0.000607

AC:

AN:

39514

South Asian (SAS)

AF:

0.000279

AC:

AN:

85874

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53324

Middle Eastern (MID)

AF:

0.000347

AC:

AN:

5758

European-Non Finnish (NFE)

AF:

0.000202

AC:

224

AN:

1110078

Other (OTH)

AF:

0.000398

AC:

AN:

60256

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.439

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.000105

AC:

AN:

151952

Hom.:

Cov.:

AF XY:

0.000108

AC XY:

AN XY:

74246

show subpopulations

African (AFR)

AF:

0.0000241

AC:

AN:

41462

American (AMR)

AF:

0.000262

AC:

AN:

15248

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3466

East Asian (EAS)

AF:

0.00

AC:

AN:

5172

South Asian (SAS)

AF:

0.00

AC:

AN:

4812

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10508

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000162

AC:

AN:

67968

Other (OTH)

AF:

0.00

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.472

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.000172

Hom.:

Bravo

AF:

0.000174

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000233

AC:

ExAC

AF:

0.000346

AC:

EpiCase

AF:

0.000329

EpiControl

AF:

0.000475

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Uncertain:2

Nov 01, 2024

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant summary: VPS13A c.398C>T (p.Pro133Leu) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00028 in 249580 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in VPS13A causing Choreoacanthocytosis (0.00028 vs 0.0011), allowing no conclusion about variant significance. To our knowledge, no occurrence of c.398C>T in individuals affected with Choreoacanthocytosis and no experimental evidence demonstrating its impact on protein function have been reported. ClinVar contains an entry for this variant (Variation ID: 448860). Based on the evidence outlined above, the variant was classified as uncertain significance. -

Feb 07, 2017

Athena Diagnostics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Uncertain:1

Aug 20, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 133 of the VPS13A protein (p.Pro133Leu). This variant is present in population databases (rs202090510, gnomAD 0.06%). This variant has not been reported in the literature in individuals affected with VPS13A-related conditions. ClinVar contains an entry for this variant (Variation ID: 448860). 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. 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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.071

BayesDel_addAF

Benign

-0.53

BayesDel_noAF

Benign

-0.64

CADD

Benign

8.1

(source)

DANN

Benign

0.38

DEOGEN2

Benign

0.29

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

Eigen

Benign

-1.3

Eigen_PC

Benign

-1.3

FATHMM_MKL

Benign

0.0097

LIST_S2

Benign

0.78

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

M_CAP

Benign

0.0046

MetaRNN

Benign

0.014

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

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.20

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

PhyloP100

0.39

PrimateAI

Benign

0.22

PROVEAN

Benign

-0.91

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

REVEL

Benign

0.023

Sift

Benign

0.17

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

Sift4G

Benign

0.22

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

Polyphen

0.0

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

Vest4

0.067

MVP

0.23

MPC

0.13

ClinPred

0.0075

GERP RS

2.0

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.026

gMVP

0.19

Mutation Taster

=99/1

polymorphism

(source)

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

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

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over