NM_033305.3:c.5917G>A

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.5917G>A(p.Val1973Ile) variant causes a missense change. The variant allele was found at a frequency of 0.0114 in 1,613,484 control chromosomes in the GnomAD database, including 127 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0093 ( 7 hom., cov: 32)

Exomes 𝑓: 0.012 ( 120 hom. )

Consequence

VPS13A
NM_033305.3 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7

Conservation

PhyloP100: 6.91

Publications

10 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=0.0056748986).

BP6

Variant 9-77323153-G-A is Benign according to our data. Variant chr9-77323153-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 586931.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 = 0.00929 (1414/152166) while in subpopulation NFE AF = 0.012 (817/67944). AF 95% confidence interval is 0.0113. There are 7 homozygotes in GnomAd4. There are 636 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 7 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
VPS13A	NM_033305.3 link	c.5917G>A	p.Val1973Ile	missense_variant	Exon 45 of 72	ENST00000360280.8	NP_150648.2	Q96RL7-1
VPS13A	NM_001018037.2 link	c.5800G>A	p.Val1934Ile	missense_variant	Exon 44 of 71		NP_001018047.1	Q96RL7-3
VPS13A	NM_015186.4 link	c.5917G>A	p.Val1973Ile	missense_variant	Exon 45 of 69		NP_056001.1	Q96RL7-2
VPS13A	NM_001018038.3 link	c.5917G>A	p.Val1973Ile	missense_variant	Exon 45 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.5917G>A	p.Val1973Ile	missense_variant	Exon 45 of 72	1	NM_033305.3	ENSP00000353422.3		Q96RL7-1

Frequencies

GnomAD3 genomes

AF:

0.00931

AC:

1416

AN:

152048

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00879

Gnomad AMI

AF:

0.00329

Gnomad AMR

AF:

0.00525

Gnomad ASJ

AF:

0.0184

Gnomad EAS

AF:

0.000192

Gnomad SAS

AF:

0.00331

Gnomad FIN

AF:

0.00292

Gnomad MID

AF:

0.0601

Gnomad NFE

AF:

0.0120

Gnomad OTH

AF:

0.0101

GnomAD2 exomes

AF:

0.00932

AC:

2338

AN:

250958

AF XY:

0.00952

show subpopulations

Gnomad AFR exome

AF:

0.00923

Gnomad AMR exome

AF:

0.00513

Gnomad ASJ exome

AF:

0.0203

Gnomad EAS exome

AF:

0.000109

Gnomad FIN exome

AF:

0.00421

Gnomad NFE exome

AF:

0.0136

Gnomad OTH exome

AF:

0.0138

GnomAD4 exome

AF:

0.0116

AC:

16956

AN:

1461318

Hom.:

120

Cov.:

AF XY:

0.0115

AC XY:

8340

AN XY:

726934

show subpopulations

African (AFR)

AF:

0.0107

AC:

359

AN:

33452

American (AMR)

AF:

0.00548

AC:

245

AN:

44668

Ashkenazi Jewish (ASJ)

AF:

0.0216

AC:

563

AN:

26112

East Asian (EAS)

AF:

0.0000756

AC:

AN:

39658

South Asian (SAS)

AF:

0.00352

AC:

304

AN:

86250

European-Finnish (FIN)

AF:

0.00502

AC:

268

AN:

53394

Middle Eastern (MID)

AF:

0.0480

AC:

277

AN:

5766

European-Non Finnish (NFE)

AF:

0.0128

AC:

14245

AN:

1111646

Other (OTH)

AF:

0.0115

AC:

692

AN:

60372

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.457

Heterozygous variant carriers

861

1722

2582

3443

4304

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

538

1076

1614

2152

2690

<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:

0.00929

AC:

1414

AN:

152166

Hom.:

Cov.:

AF XY:

0.00855

AC XY:

636

AN XY:

74402

show subpopulations

African (AFR)

AF:

0.00874

AC:

363

AN:

41544

American (AMR)

AF:

0.00524

AC:

AN:

15272

Ashkenazi Jewish (ASJ)

AF:

0.0184

AC:

AN:

3470

East Asian (EAS)

AF:

0.000193

AC:

AN:

5184

South Asian (SAS)

AF:

0.00331

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.00292

AC:

AN:

10608

Middle Eastern (MID)

AF:

0.0612

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0120

AC:

817

AN:

67944

Other (OTH)

AF:

0.00995

AC:

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.495

Heterozygous variant carriers

146

219

292

365

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

<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:

0.0125

Hom.:

Bravo

AF:

0.0102

TwinsUK

AF:

0.0129

AC:

ALSPAC

AF:

0.0140

AC:

ESP6500AA

AF:

0.00953

AC:

ESP6500EA

AF:

0.0136

AC:

117

ExAC

AF:

0.00930

AC:

1129

Asia WGS

AF:

0.00347

AC:

AN:

3476

EpiCase

AF:

0.0141

EpiControl

AF:

0.0134

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:7

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

- -

Jan 20, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jun 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

VPS13A: BP4, BS1, BS2 -

Dec 01, 2020

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Chorea-acanthocytosis

Benign:2

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: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 benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Nov 27, 2019

Natera, Inc.

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

not specified

Benign:1

Feb 01, 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

0.11

BayesDel_addAF

Benign

-0.49

BayesDel_noAF

Benign

-0.47

CADD

Uncertain

(source)

DANN

Uncertain

0.98

DEOGEN2

Benign

0.19

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

Eigen

Uncertain

0.35

Eigen_PC

Uncertain

0.42

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.86

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

MetaRNN

Benign

0.0057

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

MetaSVM

Benign

-0.97

MutationAssessor

Uncertain

2.7

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

PhyloP100

6.9

PrimateAI

Benign

0.43

PROVEAN

Benign

-0.52

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

REVEL

Benign

0.16

Sift

Benign

0.41

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

Sift4G

Benign

0.42

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

Polyphen

0.91

P;B;D;P;P;P;D

Vest4

0.33

MVP

0.54

MPC

0.27

ClinPred

0.034

GERP RS

4.8

Varity_R

0.050

gMVP

0.36

Mutation Taster

=100/0

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

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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