9-77252265-G-A

Variant names:

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_033305.3(VPS13A):c.2201G>A(p.Ser734Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00144 in 1,613,974 control chromosomes in the GnomAD database, including 5 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 Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. S734S) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.00087 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0015 ( 5 hom. )

Consequence

VPS13A
NM_033305.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:5B:4

Conservation

PhyloP100: 0.738

Publications

6 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 -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0054429173).

BP6

Variant 9-77252265-G-A is Benign according to our data. Variant chr9-77252265-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 367364.

BS1

Variant frequency is greater than expected in population nfe. GnomAdExome4 allele frequency = 0.00149 (2184/1461678) while in subpopulation NFE AF = 0.00189 (2102/1111860). AF 95% confidence interval is 0.00182. There are 5 homozygotes in GnomAdExome4. There are 1053 alleles in the male GnomAdExome4 subpopulation. Median coverage is 31. This position passed quality control check.

BS2

High Homozygotes in GnomAdExome4 at 5 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
VPS13A	NM_033305.3 link	c.2201G>A	p.Ser734Asn	missense_variant	Exon 22 of 72	ENST00000360280.8	NP_150648.2	Q96RL7-1
VPS13A	NM_001018037.2 link	c.2201G>A	p.Ser734Asn	missense_variant	Exon 22 of 71		NP_001018047.1	Q96RL7-3
VPS13A	NM_015186.4 link	c.2201G>A	p.Ser734Asn	missense_variant	Exon 22 of 69		NP_056001.1	Q96RL7-2
VPS13A	NM_001018038.3 link	c.2201G>A	p.Ser734Asn	missense_variant	Exon 22 of 69		NP_001018048.1	Q96RL7-4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
VPS13A	ENST00000360280.8 link	c.2201G>A	p.Ser734Asn	missense_variant	Exon 22 of 72	1	NM_033305.3	ENSP00000353422.3	Q96RL7-1
VPS13A	ENST00000376636.7 link	c.2201G>A	p.Ser734Asn	missense_variant	Exon 22 of 71	1		ENSP00000365823.3	Q96RL7-3
VPS13A	ENST00000643348.1 link	c.2201G>A	p.Ser734Asn	missense_variant	Exon 22 of 69			ENSP00000493592.1	Q96RL7-2
VPS13A	ENST00000645632.1 link	c.2201G>A	p.Ser734Asn	missense_variant	Exon 22 of 69			ENSP00000496361.1	Q96RL7-4

Frequencies

GnomAD3 genomes

AF:

0.000874

AC:

133

AN:

152178

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000362

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000131

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000415

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00166

Gnomad OTH

AF:

0.000478

GnomAD2 exomes

AF:

0.000632

AC:

159

AN:

251434

AF XY:

0.000692

show subpopulations

Gnomad AFR exome

AF:

0.000185

Gnomad AMR exome

AF:

0.000202

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0000462

Gnomad NFE exome

AF:

0.00126

Gnomad OTH exome

AF:

0.000163

GnomAD4 exome

AF:

0.00149

AC:

2184

AN:

1461678

Hom.:

Cov.:

AF XY:

0.00145

AC XY:

1053

AN XY:

727146

show subpopulations

African (AFR)

AF:

0.000239

AC:

AN:

33476

American (AMR)

AF:

0.000134

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26128

East Asian (EAS)

AF:

0.00

AC:

AN:

39672

South Asian (SAS)

AF:

0.000186

AC:

AN:

86252

European-Finnish (FIN)

AF:

0.000112

AC:

AN:

53414

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5766

European-Non Finnish (NFE)

AF:

0.00189

AC:

2102

AN:

1111860

Other (OTH)

AF:

0.000762

AC:

AN:

60386

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.458

Heterozygous variant carriers

100

200

300

400

500

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

184

276

368

460

<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:

0.000873

AC:

133

AN:

152296

Hom.:

Cov.:

AF XY:

0.000806

AC XY:

AN XY:

74464

show subpopulations

African (AFR)

AF:

0.000361

AC:

AN:

41586

American (AMR)

AF:

0.000131

AC:

AN:

15286

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5186

South Asian (SAS)

AF:

0.000415

AC:

AN:

4820

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10610

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00166

AC:

113

AN:

68016

Other (OTH)

AF:

0.000473

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

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:

0.00108

Hom.:

Bravo

AF:

0.000684

TwinsUK

AF:

0.00108

AC:

ALSPAC

AF:

0.00311

AC:

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.000930

AC:

ExAC

AF:

0.000511

AC:

EpiCase

AF:

0.00147

EpiControl

AF:

0.00113

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:5Benign:4

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Chorea-acanthocytosis

Uncertain:2Benign:1

Jun 05, 2020

Natera, Inc.

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance:Uncertain significance

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, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

Oct 31, 2018

Fulgent Genetics, Fulgent Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Uncertain:2Benign:1

Sep 14, 2020

GeneDx

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Aug 16, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces serine, which is neutral and polar, with asparagine, which is neutral and polar, at codon 734 of the VPS13A protein (p.Ser734Asn). This variant is present in population databases (rs117320408, gnomAD 0.1%), and has an allele count higher than expected for a pathogenic variant. 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: 367364). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The asparagine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. 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 01, 2022

CeGaT Center for Human Genetics Tuebingen

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

VPS13A: PM2, BP4 -

not specified

Uncertain:1Benign:1

Mar 07, 2017

Athena Diagnostics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jul 03, 2024

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

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant summary: VPS13A c.2201G>A (p.Ser734Asn) results in a conservative amino acid change located in the middle RBG modules region (IPR031642) of the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.0014 in 1607002 control chromosomes in the gnomAD database (v4.1 dataset), including 5 homozygotes. The observed variant frequency is approximately 1.3-fold of the estimated maximal expected allele frequency for a pathogenic variant in VPS13A causing Choreoacanthocytosis phenotype (0.0011). To our knowledge, no occurrence of c.2201G>A 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: 367364). Based on the evidence outlined above, the variant was classified as likely benign. -

Inborn genetic diseases

Benign:1

Sep 01, 2021

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

0.051

BayesDel_addAF

Benign

-0.69

BayesDel_noAF

Benign

-0.77

CADD

Benign

(source)

DANN

Benign

0.28

DEOGEN2

Benign

0.064

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

Eigen

Benign

-0.89

Eigen_PC

Benign

-0.70

FATHMM_MKL

Benign

0.046

LIST_S2

Benign

0.44

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

M_CAP

Benign

0.0032

MetaRNN

Benign

0.0054

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

MetaSVM

Benign

-1.0

MutationAssessor

Benign

-1.4

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

PhyloP100

0.74

PrimateAI

Benign

0.34

PROVEAN

Benign

0.80

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

REVEL

Benign

0.025

Sift

Benign

1.0

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

Sift4G

Benign

0.38

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

Polyphen

0.0

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

Vest4

0.11

MVP

0.25

MPC

0.12

ClinPred

0.0018

GERP RS

-0.073

Varity_R

0.020

gMVP

0.068

Mutation Taster

=93/7

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