15-90999015-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP3

The NM_018668.5(VPS33B):​c.1814G>A​(p.Ser605Asn) variant causes a missense change. The variant allele was found at a frequency of 0.00000137 in 1,461,882 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. S605S) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 32)
Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

VPS33B
NM_018668.5 missense

Scores

3
8
8

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 6.50
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 3 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.833

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
VPS33BNM_018668.5 linkuse as main transcriptc.1814G>A p.Ser605Asn missense_variant 23/23 ENST00000333371.8

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
VPS33BENST00000333371.8 linkuse as main transcriptc.1814G>A p.Ser605Asn missense_variant 23/231 NM_018668.5 P1Q9H267-1
VPS33BENST00000535906.1 linkuse as main transcriptc.1733G>A p.Ser578Asn missense_variant 22/222
VPS33BENST00000557470.5 linkuse as main transcriptn.187G>A non_coding_transcript_exon_variant 3/35
VPS33BENST00000574755.5 linkuse as main transcriptc.*1509G>A 3_prime_UTR_variant, NMD_transcript_variant 22/222

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD3 exomes
AF:
0.00000796
AC:
2
AN:
251394
Hom.:
0
AF XY:
0.0000147
AC XY:
2
AN XY:
135876
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.0000544
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00000879
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.00000137
AC:
2
AN:
1461882
Hom.:
0
Cov.:
30
AF XY:
0.00000138
AC XY:
1
AN XY:
727240
show subpopulations
Gnomad4 AFR exome
AF:
0.00
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:
0.00
Gnomad4 NFE exome
AF:
8.99e-7
Gnomad4 OTH exome
AF:
0.0000166
GnomAD4 genome
Cov.:
32
ExAC
AF:
0.0000165
AC:
2

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

Inborn genetic diseases Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingAmbry GeneticsJun 07, 2023The c.1814G>A (p.S605N) alteration is located in exon 23 (coding exon 23) of the VPS33B gene. This alteration results from a G to A substitution at nucleotide position 1814, causing the serine (S) at amino acid position 605 to be replaced by an asparagine (N). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.61
BayesDel_addAF
Benign
-0.10
T
BayesDel_noAF
Benign
-0.21
CADD
Uncertain
24
DANN
Uncertain
1.0
DEOGEN2
Benign
0.37
T;.
Eigen
Uncertain
0.39
Eigen_PC
Uncertain
0.49
FATHMM_MKL
Pathogenic
0.99
D
LIST_S2
Uncertain
0.91
D;D
M_CAP
Benign
0.044
D
MetaRNN
Pathogenic
0.83
D;D
MetaSVM
Uncertain
-0.15
T
MutationAssessor
Uncertain
2.1
M;.
MutationTaster
Benign
1.0
D;D;D
PrimateAI
Uncertain
0.62
T
PROVEAN
Benign
-0.25
N;N
REVEL
Uncertain
0.44
Sift
Benign
0.079
T;T
Sift4G
Benign
0.074
T;T
Polyphen
0.64
P;P
Vest4
0.48
MutPred
0.91
Loss of disorder (P = 0.126);.;
MVP
0.74
MPC
0.58
ClinPred
0.59
D
GERP RS
5.8
Varity_R
0.21
gMVP
0.84

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: rs768648295; hg19: chr15-91542245; API