dbSNP rs149840356: VPS13A:p.Tyr1587Cys (chr9-77316303-A-G) – 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.4760A>G(p.Tyr1587Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00828 in 1,613,384 control chromosomes in the GnomAD database, including 73 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Y1587S) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0053 ( 3 hom., cov: 32)

Exomes 𝑓: 0.0086 ( 70 hom. )

Consequence

VPS13A
NM_033305.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:10O:1

Conservation

PhyloP100: 2.71

Publications

8 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, Ambry Genetics, Genomics England PanelApp, Labcorp Genetics (formerly Invitae)

VPS13A links:

Genome browser will be placed here

new If you want to explore the variant's impact on the transcript NM_033305.3, check out the Mutation Effect Viewer. This is especially useful for frameshift variants or if you want to visualize the effect of exon loss / intron retention.

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0065418184).

BP6

Variant 9-77316303-A-G is Benign according to our data. Variant chr9-77316303-A-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 448864.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00527 (802/152172) while in subpopulation NFE AF = 0.00949 (645/67936). AF 95% confidence interval is 0.00889. There are 3 homozygotes in GnomAd4. There are 360 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 3 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	UniProt
VPS13A	NM_033305.3	MANE Select	c.4760A>G	p.Tyr1587Cys	missense	Exon 39 of 72	NP_150648.2	Q96RL7-1
VPS13A	NM_001018037.2		c.4643A>G	p.Tyr1548Cys	missense	Exon 38 of 71	NP_001018047.1	Q96RL7-3
VPS13A	NM_015186.4		c.4760A>G	p.Tyr1587Cys	missense	Exon 39 of 69	NP_056001.1	Q96RL7-2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
VPS13A	ENST00000360280.8	TSL:1 MANE Select	c.4760A>G	p.Tyr1587Cys	missense	Exon 39 of 72	ENSP00000353422.3	Q96RL7-1
VPS13A	ENST00000376636.7	TSL:1	c.4643A>G	p.Tyr1548Cys	missense	Exon 38 of 71	ENSP00000365823.3	Q96RL7-3
VPS13A	ENST00000643348.1		c.4760A>G	p.Tyr1587Cys	missense	Exon 39 of 69	ENSP00000493592.1	Q96RL7-2

Frequencies

GnomAD3 genomes

AF:

0.00527

AC:

802

AN:

152054

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00164

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00229

Gnomad ASJ

AF:

0.00375

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00414

Gnomad FIN

AF:

0.00141

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00949

Gnomad OTH

AF:

0.00287

GnomAD2 exomes

AF:

0.00457

AC:

1149

AN:

251150

AF XY:

0.00476

show subpopulations

Gnomad AFR exome

AF:

0.00123

Gnomad AMR exome

AF:

0.00127

Gnomad ASJ exome

AF:

0.00487

Gnomad EAS exome

AF:

0.0000544

Gnomad FIN exome

AF:

0.00171

Gnomad NFE exome

AF:

0.00766

Gnomad OTH exome

AF:

0.00474

GnomAD4 exome

AF:

0.00860

AC:

12564

AN:

1461212

Hom.:

Cov.:

AF XY:

0.00833

AC XY:

6053

AN XY:

726888

show subpopulations

African (AFR)

AF:

0.00129

AC:

AN:

33448

American (AMR)

AF:

0.00119

AC:

AN:

44718

Ashkenazi Jewish (ASJ)

AF:

0.00640

AC:

167

AN:

26106

East Asian (EAS)

AF:

0.00

AC:

AN:

39642

South Asian (SAS)

AF:

0.00380

AC:

328

AN:

86232

European-Finnish (FIN)

AF:

0.00200

AC:

107

AN:

53406

Middle Eastern (MID)

AF:

0.00121

AC:

AN:

5764

European-Non Finnish (NFE)

AF:

0.0103

AC:

11446

AN:

1111536

Other (OTH)

AF:

0.00684

AC:

413

AN:

60360

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.482

Heterozygous variant carriers

654

1308

1963

2617

3271

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

458

916

1374

1832

2290

<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:

0.00527

AC:

802

AN:

152172

Hom.:

Cov.:

AF XY:

0.00484

AC XY:

360

AN XY:

74402

show subpopulations

African (AFR)

AF:

0.00164

AC:

AN:

41558

American (AMR)

AF:

0.00229

AC:

AN:

15280

Ashkenazi Jewish (ASJ)

AF:

0.00375

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5170

South Asian (SAS)

AF:

0.00415

AC:

AN:

4824

European-Finnish (FIN)

AF:

0.00141

AC:

AN:

10616

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00949

AC:

645

AN:

67936

Other (OTH)

AF:

0.00284

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

125

166

208

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

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:

0.00675

Hom.:

Bravo

AF:

0.00480

Asia WGS

AF:

0.000867

AC:

AN:

3476

EpiCase

AF:

0.00786

EpiControl

AF:

0.00806

ClinVar

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (5)

Chorea-acanthocytosis (5)

not specified (2)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.052

BayesDel_addAF

Benign

-0.56

BayesDel_noAF

Benign

-0.57

CADD

Benign

(source)

DANN

Benign

0.88

DEOGEN2

Benign

0.28

Eigen

Benign

-0.89

Eigen_PC

Benign

-0.73

FATHMM_MKL

Benign

0.21

LIST_S2

Benign

0.79

MetaRNN

Benign

0.0065

MetaSVM

Benign

-1.0

MutationAssessor

Benign

-0.51

PhyloP100

2.7

PrimateAI

Benign

0.25

PROVEAN

Benign

-0.99

REVEL

Benign

0.069

Sift

Benign

0.13

Sift4G

Benign

0.093

Varity_R

0.064

gMVP

0.62

Mutation Taster

=100/0

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

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