rs41289969

Positions:

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_033305.3(VPS13A):c.5917G>A(p.Val1973Ile) variant causes a missense change. The variant allele was found at a frequency of 0.0114 in 1,613,484 control chromosomes in the GnomAD database, including 127 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0093 ( 7 hom., cov: 32)

Exomes 𝑓: 0.012 ( 120 hom. )

Consequence

VPS13A
NM_033305.3 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7

Conservation

PhyloP100: 6.91

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 -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0056748986).

BP6

Variant 9-77323153-G-A is Benign according to our data. Variant chr9-77323153-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 586931.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-77323153-G-A is described in Lovd as [Benign]. Variant chr9-77323153-G-A is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00929 (1414/152166) while in subpopulation NFE AF= 0.012 (817/67944). AF 95% confidence interval is 0.0113. There are 7 homozygotes in gnomad4. There are 636 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 7 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
VPS13A	NM_033305.3 linkuse as main transcript	c.5917G>A	p.Val1973Ile	missense_variant	45/72	ENST00000360280.8	NP_150648.2	Q96RL7-1
VPS13A	NM_001018037.2 linkuse as main transcript	c.5800G>A	p.Val1934Ile	missense_variant	44/71		NP_001018047.1	Q96RL7-3
VPS13A	NM_015186.4 linkuse as main transcript	c.5917G>A	p.Val1973Ile	missense_variant	45/69		NP_056001.1	Q96RL7-2
VPS13A	NM_001018038.3 linkuse as main transcript	c.5917G>A	p.Val1973Ile	missense_variant	45/69		NP_001018048.1	Q96RL7-4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
VPS13A	ENST00000360280.8 linkuse as main transcript	c.5917G>A	p.Val1973Ile	missense_variant	45/72	1	NM_033305.3	ENSP00000353422.3		Q96RL7-1

Frequencies

GnomAD3 genomes

AF:

0.00931

AC:

1416

AN:

152048

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00879

Gnomad AMI

AF:

0.00329

Gnomad AMR

AF:

0.00525

Gnomad ASJ

AF:

0.0184

Gnomad EAS

AF:

0.000192

Gnomad SAS

AF:

0.00331

Gnomad FIN

AF:

0.00292

Gnomad MID

AF:

0.0601

Gnomad NFE

AF:

0.0120

Gnomad OTH

AF:

0.0101

GnomAD3 exomes

AF:

0.00932

AC:

2338

AN:

250958

Hom.:

AF XY:

0.00952

AC XY:

1291

AN XY:

135606

show subpopulations

Gnomad AFR exome

AF:

0.00923

Gnomad AMR exome

AF:

0.00513

Gnomad ASJ exome

AF:

0.0203

Gnomad EAS exome

AF:

0.000109

Gnomad SAS exome

AF:

0.00291

Gnomad FIN exome

AF:

0.00421

Gnomad NFE exome

AF:

0.0136

Gnomad OTH exome

AF:

0.0138

GnomAD4 exome

AF:

0.0116

AC:

16956

AN:

1461318

Hom.:

120

Cov.:

AF XY:

0.0115

AC XY:

8340

AN XY:

726934

show subpopulations

Gnomad4 AFR exome

AF:

0.0107

Gnomad4 AMR exome

AF:

0.00548

Gnomad4 ASJ exome

AF:

0.0216

Gnomad4 EAS exome

AF:

0.0000756

Gnomad4 SAS exome

AF:

0.00352

Gnomad4 FIN exome

AF:

0.00502

Gnomad4 NFE exome

AF:

0.0128

Gnomad4 OTH exome

AF:

0.0115

GnomAD4 genome

AF:

0.00929

AC:

1414

AN:

152166

Hom.:

Cov.:

AF XY:

0.00855

AC XY:

636

AN XY:

74402

show subpopulations

Gnomad4 AFR

AF:

0.00874

Gnomad4 AMR

AF:

0.00524

Gnomad4 ASJ

AF:

0.0184

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.00331

Gnomad4 FIN

AF:

0.00292

Gnomad4 NFE

AF:

0.0120

Gnomad4 OTH

AF:

0.00995

Alfa

AF:

0.0133

Hom.:

Bravo

AF:

0.0102

TwinsUK

AF:

0.0129

AC:

ALSPAC

AF:

0.0140

AC:

ESP6500AA

AF:

0.00953

AC:

ESP6500EA

AF:

0.0136

AC:

117

ExAC

AF:

0.00930

AC:

1129

Asia WGS

AF:

0.00347

AC:

AN:

3476

EpiCase

AF:

0.0141

EpiControl

AF:

0.0134

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:4

Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Dec 01, 2020	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Sep 01, 2024	VPS13A: BP4, BS1, BS2 -

Chorea-acanthocytosis

Benign:2

Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Nov 27, 2019	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 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 benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

not specified

Benign:1

Benign, criteria provided, single submitter

clinical testing

Athena Diagnostics

Feb 01, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Benign

-0.49

BayesDel_noAF

Benign

-0.47

CADD

Uncertain

DANN

Uncertain

0.98

DEOGEN2

Benign

0.19

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

Eigen

Uncertain

0.35

Eigen_PC

Uncertain

0.42

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.86

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

MetaRNN

Benign

0.0057

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

MetaSVM

Benign

-0.97

MutationAssessor

Uncertain

2.7

M;.;M;M;M;M;M

PrimateAI

Benign

0.43

PROVEAN

Benign

-0.52

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

REVEL

Benign

0.16

Sift

Benign

0.41

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

Sift4G

Benign

0.42

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

Polyphen

0.91

P;B;D;P;P;P;D

Vest4

0.33

MVP

0.54

MPC

0.27

ClinPred

0.034

GERP RS

4.8

Varity_R

0.050

gMVP

0.36

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