rs41289967

Variant summary

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

The NM_033305.3(VPS13A):​c.4642G>A​(p.Glu1548Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00249 in 1,608,202 control chromosomes in the GnomAD database, including 14 homozygotes. 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 Likely benign (★★).

Frequency

Genomes: 𝑓 0.0021 ( 2 hom., cov: 32)
Exomes 𝑓: 0.0025 ( 12 hom. )

Consequence

VPS13A
NM_033305.3 missense

Scores

2
17

Clinical Significance

Likely benign criteria provided, multiple submitters, no conflicts B:11

Conservation

PhyloP100: 0.0870
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]

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=0.0038916469).
BP6
Variant 9-77316185-G-A is Benign according to our data. Variant chr9-77316185-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 448863.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-77316185-G-A is described in Lovd as [Likely_benign].
BS1
Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.00211 (320/151702) while in subpopulation AMR AF= 0.00355 (54/15220). AF 95% confidence interval is 0.00281. There are 2 homozygotes in gnomad4. There are 148 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
BS2
High Homozygotes in GnomAd4 at 2 AR gene

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
VPS13ANM_033305.3 linkuse as main transcriptc.4642G>A p.Glu1548Lys missense_variant 39/72 ENST00000360280.8 NP_150648.2 Q96RL7-1
VPS13ANM_001018037.2 linkuse as main transcriptc.4525G>A p.Glu1509Lys missense_variant 38/71 NP_001018047.1 Q96RL7-3
VPS13ANM_015186.4 linkuse as main transcriptc.4642G>A p.Glu1548Lys missense_variant 39/69 NP_056001.1 Q96RL7-2
VPS13ANM_001018038.3 linkuse as main transcriptc.4642G>A p.Glu1548Lys missense_variant 39/69 NP_001018048.1 Q96RL7-4

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
VPS13AENST00000360280.8 linkuse as main transcriptc.4642G>A p.Glu1548Lys missense_variant 39/721 NM_033305.3 ENSP00000353422.3 Q96RL7-1

Frequencies

GnomAD3 genomes
AF:
0.00211
AC:
320
AN:
151584
Hom.:
2
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.000436
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00355
Gnomad ASJ
AF:
0.00606
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.000417
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00949
Gnomad NFE
AF:
0.00315
Gnomad OTH
AF:
0.00384
GnomAD3 exomes
AF:
0.00206
AC:
514
AN:
249830
Hom.:
1
AF XY:
0.00216
AC XY:
292
AN XY:
135316
show subpopulations
Gnomad AFR exome
AF:
0.000622
Gnomad AMR exome
AF:
0.00157
Gnomad ASJ exome
AF:
0.00508
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.000262
Gnomad FIN exome
AF:
0.000139
Gnomad NFE exome
AF:
0.00322
Gnomad OTH exome
AF:
0.00411
GnomAD4 exome
AF:
0.00253
AC:
3687
AN:
1456500
Hom.:
12
Cov.:
30
AF XY:
0.00247
AC XY:
1791
AN XY:
724712
show subpopulations
Gnomad4 AFR exome
AF:
0.000510
Gnomad4 AMR exome
AF:
0.00173
Gnomad4 ASJ exome
AF:
0.00480
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.000209
Gnomad4 FIN exome
AF:
0.000319
Gnomad4 NFE exome
AF:
0.00289
Gnomad4 OTH exome
AF:
0.00322
GnomAD4 genome
AF:
0.00211
AC:
320
AN:
151702
Hom.:
2
Cov.:
32
AF XY:
0.00200
AC XY:
148
AN XY:
74120
show subpopulations
Gnomad4 AFR
AF:
0.000435
Gnomad4 AMR
AF:
0.00355
Gnomad4 ASJ
AF:
0.00606
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.000418
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.00316
Gnomad4 OTH
AF:
0.00380
Alfa
AF:
0.00285
Hom.:
4
Bravo
AF:
0.00214
TwinsUK
AF:
0.00243
AC:
9
ALSPAC
AF:
0.00234
AC:
9
ESP6500AA
AF:
0.000227
AC:
1
ESP6500EA
AF:
0.00256
AC:
22
ExAC
AF:
0.00206
AC:
250
EpiCase
AF:
0.00306
EpiControl
AF:
0.00350

ClinVar

Significance: Likely benign
Submissions summary: Benign:11
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not provided Benign:6
Likely benign, no assertion criteria providedclinical testingGenome Diagnostics Laboratory, Amsterdam University Medical Center-- -
Likely benign, criteria provided, single submitterclinical testingGeneDxJul 28, 2021- -
Likely benign, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpJan 31, 2024- -
Likely benign, no assertion criteria providedclinical testingClinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center-- -
Likely benign, criteria provided, single submitterclinical testingCeGaT Center for Human Genetics TuebingenDec 01, 2023VPS13A: BP4, BS2 -
Likely benign, criteria provided, single submitternot providedBreakthrough Genomics, Breakthrough Genomics-- -
Chorea-acanthocytosis Benign:3
Benign, no assertion criteria providedclinical testingNatera, Inc.Nov 11, 2019- -
Likely benign, no assertion criteria providedclinical testingDiagnostic Laboratory, Department of Genetics, University Medical Center Groningen-- -
Likely benign, criteria provided, single submitterclinical testingIllumina Laboratory Services, IlluminaJan 12, 2018This 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. -
not specified Benign:1
Likely benign, criteria provided, single submitterclinical testingAthena DiagnosticsOct 05, 2020- -
VPS13A-related disorder Benign:1
Likely benign, no assertion criteria providedclinical testingPreventionGenetics, part of Exact SciencesMar 01, 2021This 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
0.082
BayesDel_addAF
Benign
-0.61
T
BayesDel_noAF
Benign
-0.64
CADD
Benign
9.8
DANN
Benign
0.78
DEOGEN2
Benign
0.18
.;.;T;.;.;.;T
Eigen
Benign
-1.1
Eigen_PC
Benign
-1.1
FATHMM_MKL
Benign
0.096
N
LIST_S2
Uncertain
0.91
.;D;.;.;D;D;D
M_CAP
Benign
0.0074
T
MetaRNN
Benign
0.0039
T;T;T;T;T;T;T
MetaSVM
Benign
-1.0
T
MutationAssessor
Uncertain
2.1
M;.;M;M;M;M;M
PrimateAI
Benign
0.31
T
PROVEAN
Benign
-0.93
N;N;N;N;.;.;.
REVEL
Benign
0.045
Sift
Benign
0.44
T;T;T;T;.;.;.
Sift4G
Benign
0.56
T;T;T;T;.;.;.
Polyphen
0.13
B;B;B;B;B;B;B
Vest4
0.20
MVP
0.24
MPC
0.15
ClinPred
0.0016
T
GERP RS
-0.51
Varity_R
0.084
gMVP
0.30

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

LitVar

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

Other links and lift over

dbSNP: rs41289967; hg19: chr9-79931101; API