rs371961155

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_152564.5(VPS13B):ā€‹c.4262A>Gā€‹(p.His1421Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000133 in 1,613,620 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (ā˜…ā˜…).

Frequency

Genomes: š‘“ 0.000046 ( 0 hom., cov: 32)
Exomes š‘“: 0.00014 ( 0 hom. )

Consequence

VPS13B
NM_152564.5 missense

Scores

4
6
9

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:8

Conservation

PhyloP100: 8.99
Variant links:
Genes affected
VPS13B (HGNC:2183): (vacuolar protein sorting 13 homolog B) This gene encodes a potential transmembrane protein that may function in vesicle-mediated transport and sorting of proteins within the cell. This protein may play a role in the development and the function of the eye, hematological system, and central nervous system. Mutations in this gene have been associated with Cohen syndrome. Multiple splice variants encoding distinct isoforms have been identified for this gene. [provided by RefSeq, Jul 2008]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM2
Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
VPS13BNM_017890.5 linkuse as main transcriptc.4337A>G p.His1446Arg missense_variant 29/62 ENST00000358544.7 NP_060360.3 Q7Z7G8-1
VPS13BNM_152564.5 linkuse as main transcriptc.4262A>G p.His1421Arg missense_variant 29/62 ENST00000357162.7 NP_689777.3 Q7Z7G8-2

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
VPS13BENST00000358544.7 linkuse as main transcriptc.4337A>G p.His1446Arg missense_variant 29/621 NM_017890.5 ENSP00000351346.2 Q7Z7G8-1
VPS13BENST00000357162.7 linkuse as main transcriptc.4262A>G p.His1421Arg missense_variant 29/621 NM_152564.5 ENSP00000349685.2 Q7Z7G8-2

Frequencies

GnomAD3 genomes
AF:
0.0000460
AC:
7
AN:
152182
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.0000241
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000882
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000758
AC:
19
AN:
250518
Hom.:
0
AF XY:
0.000103
AC XY:
14
AN XY:
135458
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.0000470
Gnomad NFE exome
AF:
0.000141
Gnomad OTH exome
AF:
0.000327
GnomAD4 exome
AF:
0.000142
AC:
207
AN:
1461438
Hom.:
0
Cov.:
32
AF XY:
0.000154
AC XY:
112
AN XY:
727042
show subpopulations
Gnomad4 AFR exome
AF:
0.0000299
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.0000566
Gnomad4 NFE exome
AF:
0.000177
Gnomad4 OTH exome
AF:
0.0000994
GnomAD4 genome
AF:
0.0000460
AC:
7
AN:
152182
Hom.:
0
Cov.:
32
AF XY:
0.0000134
AC XY:
1
AN XY:
74350
show subpopulations
Gnomad4 AFR
AF:
0.0000241
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000882
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.0000559
Hom.:
0
Bravo
AF:
0.0000340
TwinsUK
AF:
0.000539
AC:
2
ALSPAC
AF:
0.000259
AC:
1
ESP6500AA
AF:
0.00
AC:
0
ESP6500EA
AF:
0.000116
AC:
1
ExAC
AF:
0.0000494
AC:
6
EpiCase
AF:
0.000218
EpiControl
AF:
0.000296

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:8
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Cohen syndrome Uncertain:3
Uncertain significance, criteria provided, single submitterclinical testingIllumina Laboratory Services, IlluminaJan 13, 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, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -
Uncertain significance, criteria provided, single submitterclinical testingFulgent Genetics, Fulgent GeneticsOct 31, 2018- -
Uncertain significance, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpAug 12, 2022This sequence change replaces histidine, which is basic and polar, with arginine, which is basic and polar, at codon 1446 of the VPS13B protein (p.His1446Arg). This variant is present in population databases (rs371961155, gnomAD 0.01%). This variant has not been reported in the literature in individuals affected with VPS13B-related conditions. ClinVar contains an entry for this variant (Variation ID: 95854). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Not Available"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Not Available"). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -
not provided Uncertain:2
Uncertain significance, criteria provided, single submitterclinical testingCeGaT Center for Human Genetics TuebingenJul 01, 2018- -
Uncertain significance, criteria provided, single submitterclinical testingEurofins Ntd Llc (ga)Apr 24, 2013- -
not specified Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingGenetic Services Laboratory, University of ChicagoOct 07, 2015- -
Inborn genetic diseases Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingAmbry GeneticsAug 02, 2021The c.4337A>G (p.H1446R) alteration is located in exon 29 (coding exon 28) of the VPS13B gene. This alteration results from a A to G substitution at nucleotide position 4337, causing the histidine (H) at amino acid position 1446 to be replaced by an arginine (R). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -
VPS13B-related disorder Uncertain:1
Uncertain significance, no assertion criteria providedclinical testingPreventionGenetics, part of Exact SciencesJul 01, 2024The VPS13B c.4262A>G variant is predicted to result in the amino acid substitution p.His1421Arg. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.013% of alleles in individuals of European (Non-Finnish) descent in gnomAD. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Uncertain
0.55
BayesDel_addAF
Benign
-0.17
T
BayesDel_noAF
Benign
-0.24
CADD
Uncertain
25
DANN
Uncertain
1.0
DEOGEN2
Benign
0.20
.;T
Eigen
Pathogenic
0.69
Eigen_PC
Pathogenic
0.71
FATHMM_MKL
Pathogenic
0.99
D
LIST_S2
Benign
0.82
T;T
M_CAP
Benign
0.056
D
MetaRNN
Uncertain
0.67
D;D
MetaSVM
Benign
-0.71
T
MutationAssessor
Benign
2.0
.;M
PrimateAI
Pathogenic
0.83
D
PROVEAN
Uncertain
-3.1
D;D
REVEL
Uncertain
0.37
Sift
Benign
0.032
D;D
Sift4G
Uncertain
0.017
D;D
Polyphen
1.0
D;D
Vest4
0.78
MVP
0.71
MPC
0.57
ClinPred
0.46
T
GERP RS
5.4
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7
Varity_R
0.44
gMVP
0.75

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: rs371961155; hg19: chr8-100523369; API