dbSNP rs149694033: VPS13A:p.Arg1962Cys (chr9-77323120-C-T) – 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.5884C>T(p.Arg1962Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00495 in 1,613,306 control chromosomes in the GnomAD database, including 27 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 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. R1962H) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0039 ( 3 hom., cov: 32)

Exomes 𝑓: 0.0051 ( 24 hom. )

Consequence

VPS13A
NM_033305.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:13

Conservation

PhyloP100: 1.13

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=0.0094463825).

BP6

Variant 9-77323120-C-T is Benign according to our data. Variant chr9-77323120-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 367395.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00392 (597/152160) while in subpopulation NFE AF = 0.00606 (412/67958). AF 95% confidence interval is 0.00558. There are 3 homozygotes in GnomAd4. There are 285 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.5884C>T	p.Arg1962Cys	missense	Exon 45 of 72	NP_150648.2	Q96RL7-1
VPS13A	NM_001018037.2		c.5767C>T	p.Arg1923Cys	missense	Exon 44 of 71	NP_001018047.1	Q96RL7-3
VPS13A	NM_015186.4		c.5884C>T	p.Arg1962Cys	missense	Exon 45 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.5884C>T	p.Arg1962Cys	missense	Exon 45 of 72	ENSP00000353422.3	Q96RL7-1
VPS13A	ENST00000376636.7	TSL:1	c.5767C>T	p.Arg1923Cys	missense	Exon 44 of 71	ENSP00000365823.3	Q96RL7-3
VPS13A	ENST00000419472.1	TSL:1	c.640C>T	p.Arg214Cys	missense	Exon 5 of 7	ENSP00000414410.1	H0Y7P8

Frequencies

GnomAD3 genomes

AF:

0.00393

AC:

598

AN:

152042

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000966

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00564

Gnomad ASJ

AF:

0.00115

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000621

Gnomad FIN

AF:

0.00302

Gnomad MID

AF:

0.00949

Gnomad NFE

AF:

0.00606

Gnomad OTH

AF:

0.00861

GnomAD2 exomes

AF:

0.00362

AC:

907

AN:

250868

AF XY:

0.00358

show subpopulations

Gnomad AFR exome

AF:

0.00111

Gnomad AMR exome

AF:

0.00386

Gnomad ASJ exome

AF:

0.00139

Gnomad EAS exome

AF:

0.0000545

Gnomad FIN exome

AF:

0.00301

Gnomad NFE exome

AF:

0.00547

Gnomad OTH exome

AF:

0.00524

GnomAD4 exome

AF:

0.00506

AC:

7394

AN:

1461146

Hom.:

Cov.:

AF XY:

0.00491

AC XY:

3566

AN XY:

726856

show subpopulations

African (AFR)

AF:

0.000957

AC:

AN:

33446

American (AMR)

AF:

0.00379

AC:

169

AN:

44644

Ashkenazi Jewish (ASJ)

AF:

0.00149

AC:

AN:

26116

East Asian (EAS)

AF:

0.0000504

AC:

AN:

39652

South Asian (SAS)

AF:

0.000916

AC:

AN:

86240

European-Finnish (FIN)

AF:

0.00300

AC:

160

AN:

53388

Middle Eastern (MID)

AF:

0.00278

AC:

AN:

5764

European-Non Finnish (NFE)

AF:

0.00593

AC:

6590

AN:

1111532

Other (OTH)

AF:

0.00509

AC:

307

AN:

60364

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.469

Heterozygous variant carriers

344

688

1032

1376

1720

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

236

472

708

944

1180

<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:

0.00392

AC:

597

AN:

152160

Hom.:

Cov.:

AF XY:

0.00383

AC XY:

285

AN XY:

74378

show subpopulations

African (AFR)

AF:

0.000963

AC:

AN:

41536

American (AMR)

AF:

0.00563

AC:

AN:

15270

Ashkenazi Jewish (ASJ)

AF:

0.00115

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5188

South Asian (SAS)

AF:

0.000622

AC:

AN:

4824

European-Finnish (FIN)

AF:

0.00302

AC:

AN:

10598

Middle Eastern (MID)

AF:

0.00680

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00606

AC:

412

AN:

67958

Other (OTH)

AF:

0.00852

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.510

Heterozygous variant carriers

130

162

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:

0.00504

Hom.:

Bravo

AF:

0.00373

Asia WGS

AF:

0.000578

AC:

AN:

3476

EpiCase

AF:

0.00682

EpiControl

AF:

0.00723

ClinVar

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (7)

Chorea-acanthocytosis (6)

not specified (1)

VPS13A-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.095

BayesDel_addAF

Benign

-0.40

BayesDel_noAF

Benign

-0.35

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.79

Eigen

Benign

-0.15

Eigen_PC

Benign

-0.058

FATHMM_MKL

Benign

0.74

LIST_S2

Uncertain

0.94

MetaRNN

Benign

0.0094

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.8

PhyloP100

1.1

PrimateAI

Benign

0.46

PROVEAN

Pathogenic

-4.9

REVEL

Benign

0.059

Sift

Benign

0.032

Sift4G

Benign

0.17

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.20

gMVP

0.68

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

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