15-91000531-C-T

Variant names:

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_018668.5(VPS33B):c.1540G>A(p.Gly514Ser) variant causes a missense change. The variant allele was found at a frequency of 0.466 in 1,613,018 control chromosomes in the GnomAD database, including 197,039 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G514R) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.59 ( 30537 hom., cov: 31)

Exomes 𝑓: 0.45 ( 166502 hom. )

Consequence

VPS33B
NM_018668.5 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:9

Conservation

PhyloP100: 4.34

Variant links:

Genes affected

VPS33B (HGNC:12712): (VPS33B late endosome and lysosome associated) Vesicle mediated protein sorting plays an important role in segregation of intracellular molecules into distinct organelles. Genetic studies in yeast have identified more than 40 vacuolar protein sorting (VPS) genes involved in vesicle transport to vacuoles. This gene is a member of the Sec-1 domain family, and encodes the human ortholog of rat Vps33b which is homologous to the yeast class C Vps33 protein. The mammalian class C vacuolar protein sorting proteins are predominantly associated with late endosomes/lysosomes, and like their yeast counterparts, may mediate vesicle trafficking steps in the endosome/lysosome pathway. Mutations in this gene are associated with arthrogryposis-renal dysfunction-cholestasis syndrome. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jan 2014]

VPS33B links:

ENSG00000284946 (HGNC:):

ENSG00000284946 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=1.6257657E-6).

BP6

Variant 15-91000531-C-T is Benign according to our data. Variant chr15-91000531-C-T is described in ClinVar as [Benign]. Clinvar id is 261041.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr15-91000531-C-T is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.969 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
VPS33B	NM_018668.5 link	c.1540G>A	p.Gly514Ser	missense_variant	Exon 20 of 23	ENST00000333371.8	NP_061138.3	Q9H267-1A0A0S2Z577

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
VPS33B	ENST00000333371.8 link	c.1540G>A	p.Gly514Ser	missense_variant	Exon 20 of 23	1	NM_018668.5	ENSP00000327650.4		Q9H267-1
ENSG00000284946	ENST00000643536.1 link	n.1540G>A		non_coding_transcript_exon_variant	Exon 20 of 35			ENSP00000494429.1		A0A2R8YDQ0

Frequencies

GnomAD3 genomes

AF:

0.592

AC:

89878

AN:

151930

Hom.:

30470

Cov.:

show subpopulations

Gnomad AFR

AF:

0.882

Gnomad AMI

AF:

0.498

Gnomad AMR

AF:

0.647

Gnomad ASJ

AF:

0.430

Gnomad EAS

AF:

0.992

Gnomad SAS

AF:

0.699

Gnomad FIN

AF:

0.413

Gnomad MID

AF:

0.535

Gnomad NFE

AF:

0.402

Gnomad OTH

AF:

0.579

GnomAD3 exomes

AF:

0.564

AC:

141763

AN:

251182

Hom.:

45570

AF XY:

0.550

AC XY:

74733

AN XY:

135762

show subpopulations

Gnomad AFR exome

AF:

0.895

Gnomad AMR exome

AF:

0.744

Gnomad ASJ exome

AF:

0.421

Gnomad EAS exome

AF:

0.997

Gnomad SAS exome

AF:

0.691

Gnomad FIN exome

AF:

0.418

Gnomad NFE exome

AF:

0.402

Gnomad OTH exome

AF:

0.503

GnomAD4 exome

AF:

0.453

AC:

661843

AN:

1460970

Hom.:

166502

Cov.:

AF XY:

0.457

AC XY:

331813

AN XY:

726748

show subpopulations

Gnomad4 AFR exome

AF:

0.904

Gnomad4 AMR exome

AF:

0.731

Gnomad4 ASJ exome

AF:

0.422

Gnomad4 EAS exome

AF:

0.997

Gnomad4 SAS exome

AF:

0.680

Gnomad4 FIN exome

AF:

0.414

Gnomad4 NFE exome

AF:

0.391

Gnomad4 OTH exome

AF:

0.496

GnomAD4 genome

AF:

0.592

AC:

90009

AN:

152048

Hom.:

30537

Cov.:

AF XY:

0.597

AC XY:

44402

AN XY:

74314

show subpopulations

Gnomad4 AFR

AF:

0.883

Gnomad4 AMR

AF:

0.648

Gnomad4 ASJ

AF:

0.430

Gnomad4 EAS

AF:

0.992

Gnomad4 SAS

AF:

0.697

Gnomad4 FIN

AF:

0.413

Gnomad4 NFE

AF:

0.402

Gnomad4 OTH

AF:

0.583

Alfa

AF:

0.457

Hom.:

20714

Bravo

AF:

0.624

TwinsUK

AF:

0.385

AC:

1429

ALSPAC

AF:

0.392

AC:

1511

ESP6500AA

AF:

0.880

AC:

3870

ESP6500EA

AF:

0.398

AC:

3422

ExAC

AF:

0.563

AC:

68336

Asia WGS

AF:

0.857

AC:

2975

AN:

3478

EpiCase

AF:

0.407

EpiControl

AF:

0.407

ClinVar

Significance: Benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:3

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided

Benign:3

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Nov 12, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Arthrogryposis, renal dysfunction, and cholestasis 1

Benign:3

Dec 05, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: 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 benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

May 28, 2019

Mendelics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.068

BayesDel_addAF

Benign

-0.46

BayesDel_noAF

Benign

-0.29

CADD

Benign

DANN

Benign

0.88

DEOGEN2

Benign

0.21

T;.

Eigen

Benign

-0.77

Eigen_PC

Benign

-0.44

FATHMM_MKL

Benign

0.14

LIST_S2

Benign

0.53

T;T

MetaRNN

Benign

0.0000016

T;T

MetaSVM

Benign

-0.93

MutationAssessor

Benign

-1.9

N;.

PrimateAI

Uncertain

0.76

PROVEAN

Benign

2.7

N;N

REVEL

Benign

0.24

Sift

Benign

1.0

T;T

Sift4G

Benign

1.0

T;T

Polyphen

0.0020

B;B

Vest4

0.076

MPC

0.15

ClinPred

0.0046

GERP RS

5.8

Varity_R

0.064

gMVP

0.34

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