dbSNP rs41289971: VPS13A:p.Arg1993Arg (chr9-77323215-C-T) – ACMG Classification: Benign (-19 pts)

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_ModerateBP6_Very_StrongBP7BS1BS2

The NM_033305.3(VPS13A):c.5979C>T(p.Arg1993Arg) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00823 in 1,613,050 control chromosomes in the GnomAD database, including 69 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0056 ( 3 hom., cov: 32)

Exomes 𝑓: 0.0085 ( 66 hom. )

Consequence

VPS13A
NM_033305.3 synonymous

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:10

Conservation

PhyloP100: 0.339

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, 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 -19 ACMG points.

BP4

Computational evidence support a benign effect (REVEL=0.121).

BP6

Variant 9-77323215-C-T is Benign according to our data. Variant chr9-77323215-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 448868.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=0.339 with no splicing effect.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00556 (846/152118) while in subpopulation NFE AF = 0.00992 (674/67952). AF 95% confidence interval is 0.0093. There are 3 homozygotes in GnomAd4. There are 379 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.5979C>T	p.Arg1993Arg	synonymous	Exon 45 of 72	NP_150648.2	Q96RL7-1
VPS13A	NM_001018037.2		c.5862C>T	p.Arg1954Arg	synonymous	Exon 44 of 71	NP_001018047.1	Q96RL7-3
VPS13A	NM_015186.4		c.5979C>T	p.Arg1993Arg	synonymous	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.5979C>T	p.Arg1993Arg	synonymous	Exon 45 of 72	ENSP00000353422.3	Q96RL7-1
VPS13A	ENST00000376636.7	TSL:1	c.5862C>T	p.Arg1954Arg	synonymous	Exon 44 of 71	ENSP00000365823.3	Q96RL7-3
VPS13A	ENST00000419472.1	TSL:1	c.735C>T	p.Arg245Arg	synonymous	Exon 5 of 7	ENSP00000414410.1	H0Y7P8

Frequencies

GnomAD3 genomes

AF:

0.00557

AC:

846

AN:

152000

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00142

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00564

Gnomad ASJ

AF:

0.00461

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.000414

Gnomad FIN

AF:

0.000283

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00992

Gnomad OTH

AF:

0.00239

GnomAD2 exomes

AF:

0.00487

AC:

1221

AN:

250832

AF XY:

0.00485

show subpopulations

Gnomad AFR exome

AF:

0.000985

Gnomad AMR exome

AF:

0.00200

Gnomad ASJ exome

AF:

0.00616

Gnomad EAS exome

AF:

0.0000544

Gnomad FIN exome

AF:

0.000555

Gnomad NFE exome

AF:

0.00877

Gnomad OTH exome

AF:

0.00360

GnomAD4 exome

AF:

0.00851

AC:

12432

AN:

1460932

Hom.:

Cov.:

AF XY:

0.00810

AC XY:

5884

AN XY:

726798

show subpopulations

African (AFR)

AF:

0.00126

AC:

AN:

33430

American (AMR)

AF:

0.00195

AC:

AN:

44686

Ashkenazi Jewish (ASJ)

AF:

0.00621

AC:

162

AN:

26106

East Asian (EAS)

AF:

0.0000252

AC:

AN:

39628

South Asian (SAS)

AF:

0.00123

AC:

106

AN:

86246

European-Finnish (FIN)

AF:

0.000656

AC:

AN:

53394

Middle Eastern (MID)

AF:

0.000347

AC:

AN:

5756

European-Non Finnish (NFE)

AF:

0.0105

AC:

11707

AN:

1111344

Other (OTH)

AF:

0.00481

AC:

290

AN:

60342

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.449

Heterozygous variant carriers

666

1332

1999

2665

3331

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

460

920

1380

1840

2300

<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:

0.00556

AC:

846

AN:

152118

Hom.:

Cov.:

AF XY:

0.00510

AC XY:

379

AN XY:

74354

show subpopulations

African (AFR)

AF:

0.00142

AC:

AN:

41536

American (AMR)

AF:

0.00564

AC:

AN:

15258

Ashkenazi Jewish (ASJ)

AF:

0.00461

AC:

AN:

3470

East Asian (EAS)

AF:

0.000194

AC:

AN:

5162

South Asian (SAS)

AF:

0.000415

AC:

AN:

4824

European-Finnish (FIN)

AF:

0.000283

AC:

AN:

10600

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00992

AC:

674

AN:

67952

Other (OTH)

AF:

0.00237

AC:

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

146

195

244

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:

0.00616

Hom.:

Bravo

AF:

0.00502

Asia WGS

AF:

0.000866

AC:

AN:

3478

EpiCase

AF:

0.00835

EpiControl

AF:

0.00771

ClinVar

ClinVar submissions

Significance:Benign/Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (5)

Chorea-acanthocytosis (3)

not specified (1)

VPS13A-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.31

CADD

Benign

6.7

(source)

DANN

Benign

0.61

PhyloP100

0.34

Mutation Taster

=100/0

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.070

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