Genetic Variant NM_018668.5:c.597C>G (chr15-91007475-G-C) – ACMG Classification: Uncertain_significance (4 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2PP3_Moderate

The NM_018668.5(VPS33B):c.597C>G(p.Cys199Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. C199C) has been classified as Benign.

Frequency

Genomes: not found (cov: 33)

Consequence

VPS33B
NM_018668.5 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.364

Publications

3 publications found

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:

VPS33B-DT (HGNC:51413): (VPS33B divergent transcript)

VPS33B-DT links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.88

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_018668.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
VPS33B	NM_018668.5	MANE Select	c.597C>G	p.Cys199Trp	missense	Exon 8 of 23	NP_061138.3
VPS33B	NM_001289148.1		c.516C>G	p.Cys172Trp	missense	Exon 7 of 22	NP_001276077.1
VPS33B	NM_001289149.1		c.324C>G	p.Cys108Trp	missense	Exon 7 of 22	NP_001276078.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
VPS33B	ENST00000333371.8	TSL:1 MANE Select	c.597C>G	p.Cys199Trp	missense	Exon 8 of 23	ENSP00000327650.4
ENSG00000284946	ENST00000643536.1		n.597C>G		non_coding_transcript_exon	Exon 8 of 35	ENSP00000494429.1
VPS33B	ENST00000535906.1	TSL:2	c.516C>G	p.Cys172Trp	missense	Exon 7 of 22	ENSP00000444053.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.95

BayesDel_addAF

Pathogenic

0.29

BayesDel_noAF

Pathogenic

0.18

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.58

Eigen

Benign

-0.083

Eigen_PC

Benign

-0.20

FATHMM_MKL

Uncertain

0.91

LIST_S2

Uncertain

0.92

M_CAP

Pathogenic

0.34

MetaRNN

Pathogenic

0.88

MetaSVM

Uncertain

-0.18

MutationAssessor

Uncertain

2.7

PhyloP100

0.36

PrimateAI

Uncertain

0.67

PROVEAN

Uncertain

-3.8

REVEL

Uncertain

0.61

Sift

Benign

0.060

Sift4G

Uncertain

0.0040

Polyphen

1.0

Vest4

0.81

MutPred

0.61

Gain of MoRF binding (P = 0.0248)

MVP

0.65

MPC

0.76

ClinPred

0.99

GERP RS

-3.4

Varity_R

0.40

gMVP

0.85

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over