rs200701326

Variant names:

• chr15-90998976-C-A
• rs200701326
• NM_018668.5:c.1853G>T

Your query was ambiguous. Multiple possible variants found:

• chr15-90998976-C-A
• chr15-90998976-C-T

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PM4

The NM_018668.5(VPS33B):​c.1853G>T​(p.Ter618Leuext*?) variant causes a stop lost change. The variant allele was found at a frequency of 0.000000684 in 1,461,804 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: VPS33B NM_018668.5 stop_lost
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 5.45
• 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 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM4: Stoplost variant in NM_018668.5 Downstream stopcodon found after 22 codons.

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.1853G>T	p.Ter618Leuext*?	stop_lost	Exon 23 of 23	NP_061138.3
	VPS33B	NM_001289148.1		c.1772G>T	p.Ter591Leuext*?	stop_lost	Exon 22 of 22	NP_001276077.1	B7Z1N4
	VPS33B	NM_001289149.1		c.1580G>T	p.Ter527Leuext*?	stop_lost	Exon 22 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.1853G>T	p.Ter618Leuext*?	stop_lost	Exon 23 of 23	ENSP00000327650.4	Q9H267-1
	ENSG00000284946	ENST00000643536.1		n.1774+701G>T		intron	N/A	ENSP00000494429.1	A0A2R8YDQ0
	VPS33B	ENST00000853125.1		c.1868G>T	p.Ter623Leuext*?	stop_lost	Exon 23 of 23	ENSP00000523184.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461804 Hom.: 0 Cov.: 30 AF XY: 0.00000138 AC XY: 1 AN XY: 727190

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44708

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26132

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

South Asian (SAS) AF: 0.00 AC: 0 AN: 86214

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

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

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1111988

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
BayesDel_addAF	Uncertain	0.051	T
BayesDel_noAF	Benign	-0.16
CADD	Benign	19
DANN	Benign	0.82
Eigen	Pathogenic	1.2
Eigen_PC	Pathogenic	1.0
FATHMM_MKL	Pathogenic	0.99	D
PhyloP100		5.5
Vest4		0.075
GERP RS		5.8

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.080		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: rs200701326; hg19: chr15-91542206;