rs149694033

Variant names:

Variant summary

Our verdict is Benign. Variant got -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. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

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:11

Conservation

PhyloP100: 1.13

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 Benign. Variant got -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 id is 367395.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=2, Benign=1, Likely_benign=4}. Variant chr9-77323120-C-T is described in Lovd as [Likely_benign]. Variant chr9-77323120-C-T is described in Lovd as [Benign].

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 male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 3 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
VPS13A	NM_033305.3 link	c.5884C>T	p.Arg1962Cys	missense_variant	Exon 45 of 72	ENST00000360280.8	NP_150648.2	Q96RL7-1
VPS13A	NM_001018037.2 link	c.5767C>T	p.Arg1923Cys	missense_variant	Exon 44 of 71		NP_001018047.1	Q96RL7-3
VPS13A	NM_015186.4 link	c.5884C>T	p.Arg1962Cys	missense_variant	Exon 45 of 69		NP_056001.1	Q96RL7-2
VPS13A	NM_001018038.3 link	c.5884C>T	p.Arg1962Cys	missense_variant	Exon 45 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.5884C>T	p.Arg1962Cys	missense_variant	Exon 45 of 72	1	NM_033305.3	ENSP00000353422.3		Q96RL7-1

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

GnomAD3 exomes

AF:

0.00362

AC:

907

AN:

250868

Hom.:

AF XY:

0.00358

AC XY:

485

AN XY:

135582

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 SAS exome

AF:

0.000752

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

Gnomad4 AFR exome

AF:

0.000957

Gnomad4 AMR exome

AF:

0.00379

Gnomad4 ASJ exome

AF:

0.00149

Gnomad4 EAS exome

AF:

0.0000504

Gnomad4 SAS exome

AF:

0.000916

Gnomad4 FIN exome

AF:

0.00300

Gnomad4 NFE exome

AF:

0.00593

Gnomad4 OTH exome

AF:

0.00509

GnomAD4 genome

AF:

0.00392

AC:

597

AN:

152160

Hom.:

Cov.:

AF XY:

0.00383

AC XY:

285

AN XY:

74378

show subpopulations

Gnomad4 AFR

AF:

0.000963

Gnomad4 AMR

AF:

0.00563

Gnomad4 ASJ

AF:

0.00115

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000622

Gnomad4 FIN

AF:

0.00302

Gnomad4 NFE

AF:

0.00606

Gnomad4 OTH

AF:

0.00852

Alfa

AF:

0.00515

Hom.:

Bravo

AF:

0.00373

TwinsUK

AF:

0.00512

AC:

ALSPAC

AF:

0.00804

AC:

ESP6500AA

AF:

0.00113

AC:

ESP6500EA

AF:

0.00640

AC:

ExAC

AF:

0.00348

AC:

422

Asia WGS

AF:

0.000578

AC:

AN:

3476

EpiCase

AF:

0.00682

EpiControl

AF:

0.00723

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2Benign:11

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Benign:6

Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Oct 01, 2024	VPS13A: BP4, BS2 -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 26, 2025	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Dec 11, 2020	- -
Likely benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Jan 08, 2019	- -

Chorea-acanthocytosis

Uncertain:2Benign:3

Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -
Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Jan 02, 2020	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Jan 15, 2019	- -
Likely benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Oct 31, 2018	- -

not specified

Benign:1

Benign, no assertion criteria provided

clinical testing

Genome Diagnostics Laboratory, Amsterdam University Medical Center

- -

VPS13A-related disorder

Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Dec 23, 2019

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.095

BayesDel_addAF

Benign

-0.40

BayesDel_noAF

Benign

-0.35

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.79

.;.;D;.;.;.;D

Eigen

Benign

-0.15

Eigen_PC

Benign

-0.058

FATHMM_MKL

Benign

0.74

LIST_S2

Uncertain

0.94

.;D;.;.;D;D;D

MetaRNN

Benign

0.0094

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

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.8

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

PrimateAI

Benign

0.46

PROVEAN

Pathogenic

-4.9

D;D;D;D;.;.;.

REVEL

Benign

0.059

Sift

Benign

0.032

D;D;D;D;.;.;.

Sift4G

Benign

0.17

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

Polyphen

0.21

B;P;B;B;B;B;B

Vest4

0.36

MVP

0.60

MPC

0.18

ClinPred

0.040

GERP RS

2.9

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.20

gMVP

0.68

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