dbSNP rs117320408: VPS13A:p.Ser734Asn (chr9-77252265-G-A) – ACMG Classification: Benign (-13 pts)

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

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_033305.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
VPS13A	NM_033305.3	MANE Select	c.2201G>A	p.Ser734Asn	missense	Exon 22 of 72	NP_150648.2
VPS13A	NM_001018037.2		c.2201G>A	p.Ser734Asn	missense	Exon 22 of 71	NP_001018047.1
VPS13A	NM_015186.4		c.2201G>A	p.Ser734Asn	missense	Exon 22 of 69	NP_056001.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
VPS13A	ENST00000360280.8	TSL:1 MANE Select	c.2201G>A	p.Ser734Asn	missense	Exon 22 of 72	ENSP00000353422.3
VPS13A	ENST00000376636.7	TSL:1	c.2201G>A	p.Ser734Asn	missense	Exon 22 of 71	ENSP00000365823.3
VPS13A	ENST00000643348.1		c.2201G>A	p.Ser734Asn	missense	Exon 22 of 69	ENSP00000493592.1

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

ClinVar submissions as Germline

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

Chorea-acanthocytosis (3)

not provided (3)

not specified (2)

Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

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

Eigen

Benign

-0.89

Eigen_PC

Benign

-0.70

FATHMM_MKL

Benign

0.046

LIST_S2

Benign

0.44

M_CAP

Benign

0.0032

MetaRNN

Benign

0.0054

MetaSVM

Benign

-1.0

MutationAssessor

Benign

-1.4

PhyloP100

0.74

PrimateAI

Benign

0.34

PROVEAN

Benign

0.80

REVEL

Benign

0.025

Sift

Benign

1.0

Sift4G

Benign

0.38

Polyphen

0.0

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over