rs149694033

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

1
3
14

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]

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
VPS13ANM_033305.3 linkc.5884C>T p.Arg1962Cys missense_variant Exon 45 of 72 ENST00000360280.8 NP_150648.2 Q96RL7-1
VPS13ANM_001018037.2 linkc.5767C>T p.Arg1923Cys missense_variant Exon 44 of 71 NP_001018047.1 Q96RL7-3
VPS13ANM_015186.4 linkc.5884C>T p.Arg1962Cys missense_variant Exon 45 of 69 NP_056001.1 Q96RL7-2
VPS13ANM_001018038.3 linkc.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
VPS13AENST00000360280.8 linkc.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.:
3
Cov.:
32
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.:
3
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.:
24
Cov.:
30
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.:
3
Cov.:
32
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.:
5
Bravo
AF:
0.00373
TwinsUK
AF:
0.00512
AC:
19
ALSPAC
AF:
0.00804
AC:
31
ESP6500AA
AF:
0.00113
AC:
5
ESP6500EA
AF:
0.00640
AC:
55
ExAC
AF:
0.00348
AC:
422
Asia WGS
AF:
0.000578
AC:
2
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
-
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center
Significance: Likely benign
Review Status: no assertion criteria provided
Collection Method: clinical testing

- -

Oct 01, 2024
CeGaT Center for Human Genetics Tuebingen
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

VPS13A: BP4, BS2 -

-
Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)
Significance: Likely benign
Review Status: no assertion criteria provided
Collection Method: clinical testing

- -

Jan 26, 2025
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Dec 11, 2020
GeneDx
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Jan 08, 2019
Athena Diagnostics
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Chorea-acanthocytosis Uncertain:2Benign:3
Jan 12, 2018
Illumina Laboratory Services, Illumina
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

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. -

Jan 02, 2020
Natera, Inc.
Significance: Benign
Review Status: no assertion criteria provided
Collection Method: clinical testing

- -

Jan 15, 2019
Revvity Omics, Revvity
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

-
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Significance: Likely benign
Review Status: no assertion criteria provided
Collection Method: clinical testing

- -

Oct 31, 2018
Fulgent Genetics, Fulgent Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

not specified Benign:1
-
Genome Diagnostics Laboratory, Amsterdam University Medical Center
Significance: Benign
Review Status: no assertion criteria provided
Collection Method: clinical testing

- -

VPS13A-related disorder Benign:1
Dec 23, 2019
PreventionGenetics, part of Exact Sciences
Significance: Likely benign
Review Status: no assertion criteria provided
Collection Method: clinical testing

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
T
BayesDel_noAF
Benign
-0.35
CADD
Benign
21
DANN
Uncertain
1.0
DEOGEN2
Uncertain
0.79
.;.;D;.;.;.;D
Eigen
Benign
-0.15
Eigen_PC
Benign
-0.058
FATHMM_MKL
Benign
0.74
D
LIST_S2
Uncertain
0.94
.;D;.;.;D;D;D
MetaRNN
Benign
0.0094
T;T;T;T;T;T;T
MetaSVM
Benign
-1.1
T
MutationAssessor
Benign
1.8
L;.;L;L;L;L;L
PrimateAI
Benign
0.46
T
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
T
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.

Other links and lift over

dbSNP: rs149694033; hg19: chr9-79938036; COSMIC: COSV100652533; COSMIC: COSV100652533; API