NM_033305.3:c.2201G>C

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_033305.3(VPS13A):c.2201G>C(p.Ser734Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000124 in 1,613,876 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S734N) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

VPS13A
NM_033305.3 missense

Scores

Clinical Significance

Not reported in ClinVar

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: Likely_benign. The variant received -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.045745313).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
VPS13A	NM_033305.3 link	c.2201G>C	p.Ser734Thr	missense_variant	Exon 22 of 72	ENST00000360280.8	NP_150648.2	Q96RL7-1
VPS13A	NM_001018037.2 link	c.2201G>C	p.Ser734Thr	missense_variant	Exon 22 of 71		NP_001018047.1	Q96RL7-3
VPS13A	NM_015186.4 link	c.2201G>C	p.Ser734Thr	missense_variant	Exon 22 of 69		NP_056001.1	Q96RL7-2
VPS13A	NM_001018038.3 link	c.2201G>C	p.Ser734Thr	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>C	p.Ser734Thr	missense_variant	Exon 22 of 72	1	NM_033305.3	ENSP00000353422.3	Q96RL7-1
VPS13A	ENST00000376636.7 link	c.2201G>C	p.Ser734Thr	missense_variant	Exon 22 of 71	1		ENSP00000365823.3	Q96RL7-3
VPS13A	ENST00000643348.1 link	c.2201G>C	p.Ser734Thr	missense_variant	Exon 22 of 69			ENSP00000493592.1	Q96RL7-2
VPS13A	ENST00000645632.1 link	c.2201G>C	p.Ser734Thr	missense_variant	Exon 22 of 69			ENSP00000496361.1	Q96RL7-4

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152178

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.00000398

AC:

AN:

251434

AF XY:

0.00

show subpopulations

Gnomad AFR exome

AF:

0.0000615

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1461698

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

727158

show subpopulations

African (AFR)

AF:

0.0000299

AC:

AN:

33476

American (AMR)

AF:

0.00

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:

0.00

AC:

AN:

86252

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53414

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5766

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1111880

Other (OTH)

AF:

0.00

AC:

AN:

60386

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152178

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74336

show subpopulations

African (AFR)

AF:

0.0000241

AC:

AN:

41464

American (AMR)

AF:

0.00

AC:

AN:

15266

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5198

South Asian (SAS)

AF:

0.00

AC:

AN:

4824

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10610

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

68024

Other (OTH)

AF:

0.00

AC:

AN:

2094

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

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:

0.00

Hom.:

Bravo

AF:

0.0000189

ExAC

AF:

0.00000824

AC:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.072

BayesDel_addAF

Benign

-0.43

BayesDel_noAF

Benign

-0.67

CADD

Benign

(source)

DANN

Benign

0.54

DEOGEN2

Benign

0.079

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

Eigen

Benign

-0.84

Eigen_PC

Benign

-0.67

FATHMM_MKL

Benign

0.40

LIST_S2

Benign

0.54

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

M_CAP

Benign

0.0050

MetaRNN

Benign

0.046

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

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.14

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

PhyloP100

0.74

PrimateAI

Benign

0.32

PROVEAN

Benign

-0.37

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

REVEL

Benign

0.015

Sift

Benign

0.73

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

Sift4G

Benign

0.24

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

Polyphen

0.0040

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

Vest4

0.14

MutPred

0.34

Loss of disorder (P = 0.0982);Loss of disorder (P = 0.0982);Loss of disorder (P = 0.0982);Loss of disorder (P = 0.0982);Loss of disorder (P = 0.0982);Loss of disorder (P = 0.0982);Loss of disorder (P = 0.0982);

MVP

0.28

MPC

0.12

ClinPred

0.019

GERP RS

-0.073

Varity_R

0.028

gMVP

0.11

Mutation Taster

=96/4

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

ClinVar

Computational scores

Splicing

Publications

Other links and lift over