rs144358567

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_033305.3(VPS13A):c.3356G>A(p.Gly1119Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00251 in 1,612,310 control chromosomes in the GnomAD database, including 26 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. G1119G) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0021 ( 2 hom., cov: 32)

Exomes 𝑓: 0.0025 ( 24 hom. )

Consequence

VPS13A
NM_033305.3 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8

Conservation

PhyloP100: 2.46

Publications

13 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: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.006241679).

BP6

Variant 9-77293357-G-A is Benign according to our data. Variant chr9-77293357-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 586929.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00214 (325/152190) while in subpopulation NFE AF = 0.00231 (157/68008). AF 95% confidence interval is 0.00201. There are 2 homozygotes in GnomAd4. There are 142 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
VPS13A	NM_033305.3 link	c.3356G>A	p.Gly1119Glu	missense_variant	Exon 32 of 72	ENST00000360280.8	NP_150648.2	Q96RL7-1
VPS13A	NM_001018037.2 link	c.3239G>A	p.Gly1080Glu	missense_variant	Exon 31 of 71		NP_001018047.1	Q96RL7-3
VPS13A	NM_015186.4 link	c.3356G>A	p.Gly1119Glu	missense_variant	Exon 32 of 69		NP_056001.1	Q96RL7-2
VPS13A	NM_001018038.3 link	c.3356G>A	p.Gly1119Glu	missense_variant	Exon 32 of 69		NP_001018048.1	Q96RL7-4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
VPS13A	ENST00000360280.8 link	c.3356G>A	p.Gly1119Glu	missense_variant	Exon 32 of 72	1	NM_033305.3	ENSP00000353422.3		Q96RL7-1

Frequencies

GnomAD3 genomes

AF:

0.00214

AC:

326

AN:

152072

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000628

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00196

Gnomad ASJ

AF:

0.0271

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000414

Gnomad FIN

AF:

0.000378

Gnomad MID

AF:

0.0127

Gnomad NFE

AF:

0.00231

Gnomad OTH

AF:

0.00431

GnomAD2 exomes

AF:

0.00310

AC:

776

AN:

250496

AF XY:

0.00303

show subpopulations

Gnomad AFR exome

AF:

0.000309

Gnomad AMR exome

AF:

0.00209

Gnomad ASJ exome

AF:

0.0245

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0000925

Gnomad NFE exome

AF:

0.00328

Gnomad OTH exome

AF:

0.00640

GnomAD4 exome

AF:

0.00255

AC:

3723

AN:

1460120

Hom.:

Cov.:

AF XY:

0.00260

AC XY:

1888

AN XY:

726380

show subpopulations

African (AFR)

AF:

0.000718

AC:

AN:

33410

American (AMR)

AF:

0.00245

AC:

109

AN:

44554

Ashkenazi Jewish (ASJ)

AF:

0.0236

AC:

616

AN:

26068

East Asian (EAS)

AF:

0.00

AC:

AN:

39502

South Asian (SAS)

AF:

0.00136

AC:

117

AN:

86048

European-Finnish (FIN)

AF:

0.000112

AC:

AN:

53374

Middle Eastern (MID)

AF:

0.00963

AC:

AN:

5714

European-Non Finnish (NFE)

AF:

0.00230

AC:

2555

AN:

1111142

Other (OTH)

AF:

0.00400

AC:

241

AN:

60308

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.459

Heterozygous variant carriers

169

338

507

676

845

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

102

204

306

408

510

<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:

0.00214

AC:

325

AN:

152190

Hom.:

Cov.:

AF XY:

0.00191

AC XY:

142

AN XY:

74404

show subpopulations

African (AFR)

AF:

0.000626

AC:

AN:

41528

American (AMR)

AF:

0.00196

AC:

AN:

15290

Ashkenazi Jewish (ASJ)

AF:

0.0271

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5176

South Asian (SAS)

AF:

0.000415

AC:

AN:

4824

European-Finnish (FIN)

AF:

0.000378

AC:

AN:

10576

Middle Eastern (MID)

AF:

0.0102

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00231

AC:

157

AN:

68008

Other (OTH)

AF:

0.00427

AC:

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.493

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

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:

0.00233

Hom.:

Bravo

AF:

0.00242

TwinsUK

AF:

0.00324

AC:

ALSPAC

AF:

0.00259

AC:

ESP6500AA

AF:

0.000908

AC:

ESP6500EA

AF:

0.00407

AC:

ExAC

AF:

0.00301

AC:

366

Asia WGS

AF:

0.00145

AC:

AN:

3474

EpiCase

AF:

0.00236

EpiControl

AF:

0.00481

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:4

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

May 30, 2019

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is associated with the following publications: (PMID: 26870756) -

Mar 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

VPS13A: BS2 -

Jan 23, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Chorea-acanthocytosis

Benign:3

Jun 10, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

Jan 07, 2020

Natera, Inc.

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

not specified

Benign:1

Nov 13, 2024

Athena Diagnostics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.21

BayesDel_addAF

Benign

-0.40

BayesDel_noAF

Benign

-0.36

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.75

.;.;D;.;.;.;D

Eigen

Benign

0.12

Eigen_PC

Benign

0.15

FATHMM_MKL

Uncertain

0.88

LIST_S2

Uncertain

0.87

.;D;.;.;D;D;D

M_CAP

Benign

0.050

MetaRNN

Benign

0.0062

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

MetaSVM

Benign

-0.68

MutationAssessor

Benign

1.9

M;.;M;M;M;M;M

PhyloP100

2.5

PrimateAI

Uncertain

0.54

PROVEAN

Uncertain

-3.8

D;D;D;D;.;.;.

REVEL

Benign

0.13

Sift

Benign

0.069

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

Sift4G

Benign

0.11

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

Polyphen

0.66

P;P;B;P;P;P;B

Vest4

0.32

MVP

0.67

MPC

0.20

ClinPred

0.051

GERP RS

3.6

Varity_R

0.27

gMVP

0.52

Mutation Taster

=93/7

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

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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