NM_033305.3:c.8225A>G

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.8225A>G(p.His2742Arg) variant causes a missense change. The variant allele was found at a frequency of 0.0000554 in 1,607,724 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00026 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000034 ( 0 hom. )

Consequence

VPS13A
NM_033305.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4B:1

Conservation

PhyloP100: 4.68

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 -4 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.020935118).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
VPS13A	NM_033305.3 link	c.8225A>G	p.His2742Arg	missense_variant	Exon 60 of 72	ENST00000360280.8	NP_150648.2	Q96RL7-1
VPS13A	NM_001018037.2 link	c.8108A>G	p.His2703Arg	missense_variant	Exon 59 of 71		NP_001018047.1	Q96RL7-3
VPS13A	NM_015186.4 link	c.8225A>G	p.His2742Arg	missense_variant	Exon 60 of 69		NP_056001.1	Q96RL7-2
VPS13A	NM_001018038.3 link	c.8225A>G	p.His2742Arg	missense_variant	Exon 60 of 69		NP_001018048.1	Q96RL7-4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
VPS13A	ENST00000360280.8 link	c.8225A>G	p.His2742Arg	missense_variant	Exon 60 of 72	1	NM_033305.3	ENSP00000353422.3	Q96RL7-1
VPS13A	ENST00000376636.7 link	c.8108A>G	p.His2703Arg	missense_variant	Exon 59 of 71	1		ENSP00000365823.3	Q96RL7-3
VPS13A	ENST00000643348.1 link	c.8225A>G	p.His2742Arg	missense_variant	Exon 60 of 69			ENSP00000493592.1	Q96RL7-2
VPS13A	ENST00000645632.1 link	c.8225A>G	p.His2742Arg	missense_variant	Exon 60 of 69			ENSP00000496361.1	Q96RL7-4

Frequencies

GnomAD3 genomes

AF:

0.000250

AC:

AN:

152114

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000845

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000131

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:

0.000478

GnomAD2 exomes

AF:

0.0000679

AC:

AN:

250430

AF XY:

0.0000590

show subpopulations

Gnomad AFR exome

AF:

0.00106

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000344

AC:

AN:

1455492

Hom.:

Cov.:

AF XY:

0.0000331

AC XY:

AN XY:

724556

show subpopulations

African (AFR)

AF:

0.00108

AC:

AN:

33304

American (AMR)

AF:

0.0000448

AC:

AN:

44660

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26042

East Asian (EAS)

AF:

0.00

AC:

AN:

39486

South Asian (SAS)

AF:

0.00

AC:

AN:

86076

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53344

Middle Eastern (MID)

AF:

0.000177

AC:

AN:

5652

European-Non Finnish (NFE)

AF:

0.00000723

AC:

AN:

1106812

Other (OTH)

AF:

0.0000499

AC:

AN:

60116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.477

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:

0.000256

AC:

AN:

152232

Hom.:

Cov.:

AF XY:

0.000309

AC XY:

AN XY:

74444

show subpopulations

African (AFR)

AF:

0.000866

AC:

AN:

41562

American (AMR)

AF:

0.000131

AC:

AN:

15300

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5178

South Asian (SAS)

AF:

0.00

AC:

AN:

4820

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10602

Middle Eastern (MID)

AF:

0.00

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

67982

Other (OTH)

AF:

0.000473

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.507

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:

0.000101

Hom.:

Bravo

AF:

0.000298

ESP6500AA

AF:

0.00159

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.0000906

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:4Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:2

Oct 22, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces histidine, which is basic and polar, with arginine, which is basic and polar, at codon 2742 of the VPS13A protein (p.His2742Arg). This variant is present in population databases (rs145686832, gnomAD 0.1%). 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: 448872). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is not expected to disrupt VPS13A protein function with a negative predictive value of 80%. 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. -

Aug 07, 2023

GeneDx

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -

not specified

Uncertain:1

Nov 23, 2016

Athena Diagnostics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Chorea-acanthocytosis

Uncertain:1

Jul 29, 2021

Fulgent Genetics, Fulgent Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Inborn genetic diseases

Benign:1

Nov 10, 2024

Ambry Genetics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.055

BayesDel_addAF

Benign

-0.49

BayesDel_noAF

Benign

-0.54

CADD

Benign

(source)

DANN

Benign

0.92

DEOGEN2

Benign

0.13

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

Eigen

Benign

-0.25

Eigen_PC

Benign

-0.051

FATHMM_MKL

Uncertain

0.97

LIST_S2

Benign

0.83

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

M_CAP

Benign

0.0079

MetaRNN

Benign

0.021

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

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.57

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

PhyloP100

4.7

PrimateAI

Benign

0.36

PROVEAN

Benign

-0.19

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

REVEL

Benign

0.024

Sift

Benign

0.15

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

Sift4G

Benign

0.17

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

Polyphen

0.031

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

Vest4

0.29

MVP

0.46

MPC

0.16

ClinPred

0.095

GERP RS

4.4

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.0

Varity_R

0.099

gMVP

0.17

Mutation Taster

=86/14

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