rs149840356

Positions:

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_033305.3(VPS13A):c.4760A>G(p.Tyr1587Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00828 in 1,613,384 control chromosomes in the GnomAD database, including 73 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 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 0.0053 ( 3 hom., cov: 32)

Exomes 𝑓: 0.0086 ( 70 hom. )

Consequence

VPS13A
NM_033305.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:8

Conservation

PhyloP100: 2.71

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=0.0065418184).

BP6

Variant 9-77316303-A-G is Benign according to our data. Variant chr9-77316303-A-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 448864.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, Likely_benign=2, Benign=3}. Variant chr9-77316303-A-G is described in Lovd as [Likely_benign]. Variant chr9-77316303-A-G is described in Lovd as [Benign].

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00527 (802/152172) while in subpopulation NFE AF= 0.00949 (645/67936). AF 95% confidence interval is 0.00889. There are 3 homozygotes in gnomad4. There are 360 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/exons	MANE	Protein	UniProt
VPS13A	NM_033305.3 link	c.4760A>G	p.Tyr1587Cys	missense_variant	39/72	ENST00000360280.8	NP_150648.2	Q96RL7-1
VPS13A	NM_001018037.2 link	c.4643A>G	p.Tyr1548Cys	missense_variant	38/71		NP_001018047.1	Q96RL7-3
VPS13A	NM_015186.4 link	c.4760A>G	p.Tyr1587Cys	missense_variant	39/69		NP_056001.1	Q96RL7-2
VPS13A	NM_001018038.3 link	c.4760A>G	p.Tyr1587Cys	missense_variant	39/69		NP_001018048.1	Q96RL7-4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
VPS13A	ENST00000360280.8 link	c.4760A>G	p.Tyr1587Cys	missense_variant	39/72	1	NM_033305.3	ENSP00000353422.3		Q96RL7-1

Frequencies

GnomAD3 genomes

AF:

0.00527

AC:

802

AN:

152054

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00164

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00229

Gnomad ASJ

AF:

0.00375

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00414

Gnomad FIN

AF:

0.00141

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00949

Gnomad OTH

AF:

0.00287

GnomAD3 exomes

AF:

0.00457

AC:

1149

AN:

251150

Hom.:

AF XY:

0.00476

AC XY:

646

AN XY:

135726

show subpopulations

Gnomad AFR exome

AF:

0.00123

Gnomad AMR exome

AF:

0.00127

Gnomad ASJ exome

AF:

0.00487

Gnomad EAS exome

AF:

0.0000544

Gnomad SAS exome

AF:

0.00327

Gnomad FIN exome

AF:

0.00171

Gnomad NFE exome

AF:

0.00766

Gnomad OTH exome

AF:

0.00474

GnomAD4 exome

AF:

0.00860

AC:

12564

AN:

1461212

Hom.:

Cov.:

AF XY:

0.00833

AC XY:

6053

AN XY:

726888

show subpopulations

Gnomad4 AFR exome

AF:

0.00129

Gnomad4 AMR exome

AF:

0.00119

Gnomad4 ASJ exome

AF:

0.00640

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00380

Gnomad4 FIN exome

AF:

0.00200

Gnomad4 NFE exome

AF:

0.0103

Gnomad4 OTH exome

AF:

0.00684

GnomAD4 genome

AF:

0.00527

AC:

802

AN:

152172

Hom.:

Cov.:

AF XY:

0.00484

AC XY:

360

AN XY:

74402

show subpopulations

Gnomad4 AFR

AF:

0.00164

Gnomad4 AMR

AF:

0.00229

Gnomad4 ASJ

AF:

0.00375

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00415

Gnomad4 FIN

AF:

0.00141

Gnomad4 NFE

AF:

0.00949

Gnomad4 OTH

AF:

0.00284

Alfa

AF:

0.00699

Hom.:

Bravo

AF:

0.00480

TwinsUK

AF:

0.00998

AC:

ALSPAC

AF:

0.00934

AC:

ESP6500AA

AF:

0.00250

AC:

ESP6500EA

AF:

0.00791

AC:

ExAC

AF:

0.00436

AC:

529

Asia WGS

AF:

0.000867

AC:

AN:

3476

EpiCase

AF:

0.00786

EpiControl

AF:

0.00806

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:8

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Benign:5

Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	May 14, 2018	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Sep 01, 2024	VPS13A: BP4, BS1, BS2 -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Oct 25, 2018	- -

Chorea-acanthocytosis

Uncertain:1Benign:2

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases was too high to be consistent with this variant causing disease. Therefore, this variant is classified as benign. -
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	Baylor Genetics	Jul 16, 2018	This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868]. -

not specified

Benign:1

Benign, no assertion criteria provided

clinical testing

Genome Diagnostics Laboratory, Amsterdam University Medical Center

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.052

BayesDel_addAF

Benign

-0.56

BayesDel_noAF

Benign

-0.57

CADD

Benign

DANN

Benign

0.88

DEOGEN2

Benign

0.28

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

Eigen

Benign

-0.89

Eigen_PC

Benign

-0.73

FATHMM_MKL

Benign

0.21

LIST_S2

Benign

0.79

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

MetaRNN

Benign

0.0065

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

MetaSVM

Benign

-1.0

MutationAssessor

Benign

-0.51

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

PrimateAI

Benign

0.25

PROVEAN

Benign

-0.99

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

REVEL

Benign

0.069

Sift

Benign

0.13

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

Sift4G

Benign

0.093

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

Polyphen

0.0

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

Vest4

0.29

MVP

0.40

MPC

0.16

ClinPred

0.0045

GERP RS

1.2

Varity_R

0.064

gMVP

0.62

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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