rs145686832

Positions:

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_033305.3(VPS13A):c.8225A>G(p.His2742Arg) variant causes a missense change. The variant allele was found at a frequency of 0.0000554 in 1,607,724 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.00026 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000034 ( 0 hom. )

Consequence

VPS13A
NM_033305.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:4

Conservation

PhyloP100: 4.68

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.020935118).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
VPS13A	NM_033305.3 linkuse as main transcript	c.8225A>G	p.His2742Arg	missense_variant	60/72	ENST00000360280.8
VPS13A	NM_001018037.2 linkuse as main transcript	c.8108A>G	p.His2703Arg	missense_variant	59/71
VPS13A	NM_015186.4 linkuse as main transcript	c.8225A>G	p.His2742Arg	missense_variant	60/69
VPS13A	NM_001018038.3 linkuse as main transcript	c.8225A>G	p.His2742Arg	missense_variant	60/69

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
VPS13A	ENST00000360280.8 linkuse as main transcript	c.8225A>G	p.His2742Arg	missense_variant	60/72	1	NM_033305.3	P4	Q96RL7-1
VPS13A	ENST00000376636.7 linkuse as main transcript	c.8108A>G	p.His2703Arg	missense_variant	59/71	1			Q96RL7-3
VPS13A	ENST00000643348.1 linkuse as main transcript	c.8225A>G	p.His2742Arg	missense_variant	60/69				Q96RL7-2
VPS13A	ENST00000645632.1 linkuse as main transcript	c.8225A>G	p.His2742Arg	missense_variant	60/69			A1	Q96RL7-4

Frequencies

GnomAD3 genomes

AF:

0.000250

AC:

AN:

152114

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000845

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000131

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:

0.000478

GnomAD3 exomes

AF:

0.0000679

AC:

AN:

250430

Hom.:

AF XY:

0.0000590

AC XY:

AN XY:

135490

show subpopulations

Gnomad AFR exome

AF:

0.00106

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS 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:

0.0000344

AC:

AN:

1455492

Hom.:

Cov.:

AF XY:

0.0000331

AC XY:

AN XY:

724556

show subpopulations

Gnomad4 AFR exome

AF:

0.00108

Gnomad4 AMR exome

AF:

0.0000448

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000723

Gnomad4 OTH exome

AF:

0.0000499

GnomAD4 genome

AF:

0.000256

AC:

AN:

152232

Hom.:

Cov.:

AF XY:

0.000309

AC XY:

AN XY:

74444

show subpopulations

Gnomad4 AFR

AF:

0.000866

Gnomad4 AMR

AF:

0.000131

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.000473

Alfa

AF:

0.0000463

Hom.:

Bravo

AF:

0.000298

ESP6500AA

AF:

0.00159

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.0000906

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	May 21, 2022	This sequence change replaces histidine, which is basic and polar, with arginine, which is basic and polar, at codon 2742 of the VPS13A protein (p.His2742Arg). This variant is present in population databases (rs145686832, gnomAD 0.1%). This variant has not been reported in the literature in individuals affected with VPS13A-related conditions. ClinVar contains an entry for this variant (Variation ID: 448872). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Aug 07, 2023	In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Athena Diagnostics

Nov 23, 2016

- -

Chorea-acanthocytosis

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Jul 29, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.055

BayesDel_addAF

Benign

-0.49

BayesDel_noAF

Benign

-0.54

CADD

Benign

DANN

Benign

0.92

DEOGEN2

Benign

0.13

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

Eigen

Benign

-0.25

Eigen_PC

Benign

-0.051

FATHMM_MKL

Uncertain

0.97

LIST_S2

Benign

0.83

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

M_CAP

Benign

0.0079

MetaRNN

Benign

0.021

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

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.57

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

MutationTaster

Benign

0.58

D;D;D;D

PrimateAI

Benign

0.36

PROVEAN

Benign

-0.19

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

REVEL

Benign

0.024

Sift

Benign

0.15

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

Sift4G

Benign

0.17

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

Polyphen

0.031

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

Vest4

0.29

MVP

0.46

MPC

0.16

ClinPred

0.095

GERP RS

4.4

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.0

Varity_R

0.099

gMVP

0.17

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over