rs140015545

Variant names:

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_017890.5(VPS13B):c.3116T>C(p.Met1039Thr) variant causes a missense change. The variant allele was found at a frequency of 0.000244 in 1,613,522 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. M1039V) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0013 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00014 ( 3 hom. )

Consequence

VPS13B
NM_017890.5 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3B:4

Conservation

PhyloP100: 5.35

Publications

2 publications found

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]

VPS13B Gene-Disease associations (from GenCC):

Cohen syndrome
Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, Myriad Women’s Health, Labcorp Genetics (formerly Invitae), G2P, Genomics England PanelApp, Laboratory for Molecular Medicine, ClinGen

VPS13B links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.00793159).

BP6

Variant 8-99431570-T-C is Benign according to our data. Variant chr8-99431570-T-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 528860.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00128 (195/152328) while in subpopulation AFR AF = 0.00433 (180/41576). AF 95% confidence interval is 0.00381. There are 0 homozygotes in GnomAd4. There are 89 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAdExome4 at 3 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
VPS13B	NM_017890.5 link	c.3116T>C	p.Met1039Thr	missense_variant	Exon 22 of 62	ENST00000358544.7	NP_060360.3
VPS13B	NM_152564.5 link	c.3116T>C	p.Met1039Thr	missense_variant	Exon 22 of 62	ENST00000357162.7	NP_689777.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
VPS13B	ENST00000358544.7 link	c.3116T>C	p.Met1039Thr	missense_variant	Exon 22 of 62	1	NM_017890.5	ENSP00000351346.2
VPS13B	ENST00000357162.7 link	c.3116T>C	p.Met1039Thr	missense_variant	Exon 22 of 62	1	NM_152564.5	ENSP00000349685.2

Frequencies

GnomAD3 genomes

AF:

0.00128

AC:

195

AN:

152210

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00434

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000785

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:

0.00

Gnomad OTH

AF:

0.00143

GnomAD2 exomes

AF:

0.000271

AC:

AN:

250890

AF XY:

0.000192

show subpopulations

Gnomad AFR exome

AF:

0.00382

Gnomad AMR exome

AF:

0.000145

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.000163

GnomAD4 exome

AF:

0.000136

AC:

198

AN:

1461194

Hom.:

Cov.:

AF XY:

0.000113

AC XY:

AN XY:

726934

show subpopulations

African (AFR)

AF:

0.00544

AC:

182

AN:

33460

American (AMR)

AF:

0.000134

AC:

AN:

44710

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26116

East Asian (EAS)

AF:

0.00

AC:

AN:

39570

South Asian (SAS)

AF:

0.0000116

AC:

AN:

86244

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53250

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5760

European-Non Finnish (NFE)

AF:

0.00000180

AC:

AN:

1111722

Other (OTH)

AF:

0.000116

AC:

AN:

60362

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00128

AC:

195

AN:

152328

Hom.:

Cov.:

AF XY:

0.00119

AC XY:

AN XY:

74480

show subpopulations

African (AFR)

AF:

0.00433

AC:

180

AN:

41576

American (AMR)

AF:

0.000784

AC:

AN:

15302

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5188

South Asian (SAS)

AF:

0.00

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10622

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

68022

Other (OTH)

AF:

0.00142

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.000414

Hom.:

Bravo

AF:

0.00143

ESP6500AA

AF:

0.00341

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.000338

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3Benign:4

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:1Benign:1

Sep 01, 2022

CeGaT Center for Human Genetics Tuebingen

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

VPS13B: BP4

Oct 01, 2020

GeneDx

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge

Cohen syndrome

Uncertain:1Benign:1

Jan 22, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Mar 30, 2021

Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

VPS13B NM_017890 exon 22 p.Met1039Thr (c.3116T>C): This variant has not been reported in the literature but is present in 0.4% (98/24028) African alleles, including 1 homozygote in the Genome Aggregation Database (http://gnomad.broadinstitute.org/rs140015545). Evolutionary conservation and computational predictive tools suggest that this variant may not impact the protein. In summary, data on this variant is insufficient for disease classification. Therefore, the clinical significance of this variant is uncertain.

not specified

Uncertain:1

Jul 27, 2021

Genetic Services Laboratory, University of Chicago

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

DNA sequence analysis of the VPS13B gene demonstrated a sequence change, c.3116T>C, in exon 22 that results in an amino acid change, p.Met1039Thr. This sequence change does not appear to have been previously described in patients with VPS13B-related disorders and has been described in the gnomAD database with a low population frequency of 0.039% (dbSNP rs140015545). The p.Met1039Thr change affects a poorly conserved amino acid residue located in a domain of the VPS13B protein that is not known to be functional. In-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL) provide contradictory results for the p.Met1039Thr substitution. Due to these contrasting evidences and the lack of functional studies, the clinical significance of the p.Met1039Thr change remains unknown at this time. Homozygous and compound heterozygous mutations in VPS13B have been identified in patients with Cohen syndrome [MIM#216550], characterized by ID, postnatal microcephaly, facial dysmorphism, pigmentary retinopathy, myopia and intermittent neutropenia.

Inborn genetic diseases

Benign:1

May 02, 2024

Ambry Genetics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.

VPS13B-related disorder

Benign:1

Dec 08, 2023

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

0.16

BayesDel_addAF

Benign

-0.47

BayesDel_noAF

Benign

-0.45

CADD

Benign

(source)

DANN

Benign

0.75

DEOGEN2

Benign

0.0

.;T

Eigen

Benign

-0.33

Eigen_PC

Benign

-0.15

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Benign

0.76

T;T

M_CAP

Benign

0.021

MetaRNN

Benign

0.0079

T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.4

L;L

PhyloP100

5.4

PrimateAI

Benign

0.37

PROVEAN

Benign

-1.2

N;N

REVEL

Benign

0.050

Sift

Uncertain

0.011

D;D

Sift4G

Uncertain

0.035

D;D

Vest4

0.37

ClinPred

0.040

GERP RS

4.7

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.49

gMVP

0.50

Mutation Taster

=94/6

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.060

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over