15-91000531-C-A

Variant names:

• chr15-91000531-C-A
• rs11073964
• NM_018668.5:c.1540G>T

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_018668.5(VPS33B):​c.1540G>T​(p.Gly514Cys) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G514S) has been classified as Benign.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: VPS33B NM_018668.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.34
• Publications: 61 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 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	VPS33B	NM_018668.5	MANE Select	c.1540G>T	p.Gly514Cys	missense	Exon 20 of 23	NP_061138.3
	VPS33B	NM_001289148.1		c.1459G>T	p.Gly487Cys	missense	Exon 19 of 22	NP_001276077.1	B7Z1N4
	VPS33B	NM_001289149.1		c.1267G>T	p.Gly423Cys	missense	Exon 19 of 22	NP_001276078.1	Q9H267-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	VPS33B	ENST00000333371.8	TSL:1 MANE Select	c.1540G>T	p.Gly514Cys	missense	Exon 20 of 23	ENSP00000327650.4	Q9H267-1
	ENSG00000284946	ENST00000643536.1		n.1540G>T		non_coding_transcript_exon	Exon 20 of 35	ENSP00000494429.1	A0A2R8YDQ0
	VPS33B	ENST00000853125.1		c.1555G>T	p.Gly519Cys	missense	Exon 20 of 23	ENSP00000523184.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1461298 Hom.: 0 Cov.: 49 AF XY: 0.00 AC XY: 0 AN XY: 726914

African (AFR) AF: 0.00 AC: 0 AN: 33468

American (AMR) AF: 0.00 AC: 0 AN: 44704

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26120

East Asian (EAS) AF: 0.00 AC: 0 AN: 39672

South Asian (SAS) AF: 0.00 AC: 0 AN: 86246

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53302

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111652

Other (OTH) AF: 0.00 AC: 0 AN: 60368

GnomAD4 genome Cov.: 31

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.47
BayesDel_addAF	Uncertain	0.044	T
BayesDel_noAF	Benign	-0.18
CADD	Uncertain	26
DANN	Uncertain	1.0
DEOGEN2	Benign	0.36	T
Eigen	Uncertain	0.23
Eigen_PC	Uncertain	0.28
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Uncertain	0.87	D
M_CAP	Pathogenic	0.51	D
MetaRNN	Uncertain	0.64	D
MetaSVM	Uncertain	0.091	D
MutationAssessor	Benign	0.90	L
PhyloP100		4.3
PrimateAI	Pathogenic	0.79	T
PROVEAN	Benign	-1.8	N
REVEL	Uncertain	0.54
Sift	Uncertain	0.0080	D
Sift4G	Uncertain	0.012	D
Polyphen		0.95	P
Vest4		0.35
MutPred		0.77		Gain of sheet (P = 0.0827)
MVP		0.79
MPC		0.48
ClinPred		0.80	D
GERP RS		5.8
Varity_R		0.26
gMVP		0.55

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

Other links and lift over

dbSNP: rs11073964; hg19: chr15-91543761;