NM_018668.5:c.357G>T

Variant names:

• chr15-91013804-C-A
• rs146758743
• NM_018668.5:c.357G>T

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP3

The NM_018668.5(VPS33B):​c.357G>T​(p.Lys119Asn) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.00000137 in 1,461,858 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. K119K) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: VPS33B NM_018668.5 missense, splice_region
• Scores: Splicing: ADA: 0.9995
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 6.00
• Publications: 0 publications found

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]

ENSG00000284946 (HGNC:):

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

ACMG classification

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. No scorers claiming Uncertain. Scorers claiming Benign: max_spliceai.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	VPS33B	NM_018668.5	MANE Select	c.357G>T	p.Lys119Asn	missense splice_region	Exon 5 of 23	NP_061138.3
	VPS33B	NM_001289148.1		c.276G>T	p.Lys92Asn	missense splice_region	Exon 4 of 22	NP_001276077.1
	VPS33B	NM_001289149.1		c.84G>T	p.Lys28Asn	missense splice_region	Exon 4 of 22	NP_001276078.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	VPS33B	ENST00000333371.8	TSL:1 MANE Select	c.357G>T	p.Lys119Asn	missense splice_region	Exon 5 of 23	ENSP00000327650.4
	ENSG00000284946	ENST00000643536.1		n.357G>T		splice_region non_coding_transcript_exon	Exon 5 of 35	ENSP00000494429.1
	VPS33B	ENST00000535906.1	TSL:2	c.276G>T	p.Lys92Asn	missense splice_region	Exon 4 of 22	ENSP00000444053.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461858 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 727234

African (AFR) AF: 0.0000299 AC: 1 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53408

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1111990

Other (OTH) AF: 0.00 AC: 0 AN: 60394

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.93
BayesDel_addAF	Uncertain	0.041	T
BayesDel_noAF	Benign	-0.18
CADD	Pathogenic	33
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.53	D
Eigen	Pathogenic	0.81
Eigen_PC	Pathogenic	0.79
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.93	D
M_CAP	Pathogenic	0.36	D
MetaRNN	Pathogenic	0.88	D
MetaSVM	Uncertain	0.11	D
MutationAssessor	Uncertain	2.6	M
PhyloP100		6.0
PrimateAI	Uncertain	0.78	T
PROVEAN	Uncertain	-3.2	D
REVEL	Uncertain	0.54
Sift	Uncertain	0.023	D
Sift4G	Uncertain	0.010	D
Polyphen		1.0	D
Vest4		0.77
MutPred		0.63		Loss of methylation at K119 (P = 0.0185)
MVP		0.92
MPC		0.68
ClinPred		0.98	D
GERP RS		5.6
Varity_R		0.54
gMVP		0.75
Mutation Taster		=14/86	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.96
SpliceAI score (max)		0.11		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs146758743; hg19: chr15-91557034;