Genetic Variant VPS13A:p.Glu1548Gln (chr9-77316185-G-C) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

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

The NM_033305.3(VPS13A):c.4642G>C(p.Glu1548Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000206 in 1,456,530 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. E1548K) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000021 ( 0 hom. )

Consequence

VPS13A
NM_033305.3 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.0870

Publications

7 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:

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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=0.03518817).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
VPS13A	NM_033305.3 link	c.4642G>C	p.Glu1548Gln	missense_variant	Exon 39 of 72	ENST00000360280.8	NP_150648.2	Q96RL7-1
VPS13A	NM_001018037.2 link	c.4525G>C	p.Glu1509Gln	missense_variant	Exon 38 of 71		NP_001018047.1	Q96RL7-3
VPS13A	NM_015186.4 link	c.4642G>C	p.Glu1548Gln	missense_variant	Exon 39 of 69		NP_056001.1	Q96RL7-2
VPS13A	NM_001018038.3 link	c.4642G>C	p.Glu1548Gln	missense_variant	Exon 39 of 69		NP_001018048.1	Q96RL7-4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
VPS13A	ENST00000360280.8 link	c.4642G>C	p.Glu1548Gln	missense_variant	Exon 39 of 72	1	NM_033305.3	ENSP00000353422.3		Q96RL7-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000400

AC:

AN:

249830

AF XY:

0.00

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000291

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:

0.00000206

AC:

AN:

1456530

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

724726

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33324

American (AMR)

AF:

0.0000224

AC:

AN:

44626

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26054

East Asian (EAS)

AF:

0.00

AC:

AN:

39568

South Asian (SAS)

AF:

0.00

AC:

AN:

85968

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53250

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5734

European-Non Finnish (NFE)

AF:

0.00000181

AC:

AN:

1107830

Other (OTH)

AF:

0.00

AC:

AN:

60176

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.458

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome 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

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000378

ExAC

AF:

0.00000824

AC:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.087

BayesDel_addAF

Benign

-0.41

BayesDel_noAF

Benign

-0.74

CADD

Benign

5.9

(source)

DANN

Benign

0.41

DEOGEN2

Benign

0.13

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

Eigen

Benign

-1.1

Eigen_PC

Benign

-1.1

FATHMM_MKL

Benign

0.13

LIST_S2

Benign

0.71

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

M_CAP

Benign

0.0059

MetaRNN

Benign

0.035

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

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.98

L;.;L;L;L;L;L

PhyloP100

0.087

PrimateAI

Benign

0.28

PROVEAN

Benign

-0.52

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

REVEL

Benign

0.041

Sift

Benign

0.40

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

Sift4G

Benign

0.50

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

Polyphen

0.0040

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

Vest4

0.079

MutPred

0.28

Loss of ubiquitination at K1551 (P = 0.0982);.;Loss of ubiquitination at K1551 (P = 0.0982);Loss of ubiquitination at K1551 (P = 0.0982);Loss of ubiquitination at K1551 (P = 0.0982);Loss of ubiquitination at K1551 (P = 0.0982);Loss of ubiquitination at K1551 (P = 0.0982);

MVP

0.31

MPC

0.13

ClinPred

0.029

GERP RS

-0.51

Varity_R

0.084

gMVP

0.30

Mutation Taster

=97/3

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.040

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