rs12899811

Positions:

• chr15-91000846-A-G
• chr15-91000846-A-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_018668.5(VPS33B):​c.1480-255T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.428 in 474,092 control chromosomes in the GnomAD database, including 51,610 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.46 (18811 hom., cov: 32)
  • Exomes 𝑓: 0.41 (32799 hom.)
• Consequence: VPS33B NM_018668.5 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.478

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]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.89).
• BP6: Variant 15-91000846-A-G is Benign according to our data. Variant chr15-91000846-A-G is described in ClinVar as [Benign]. Clinvar id is 1267440.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.947 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
VPS33B	NM_018668.5	c.1480-255T>C		intron_variant		ENST00000333371.8	NP_061138.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
VPS33B	ENST00000333371.8	c.1480-255T>C		intron_variant		1	NM_018668.5	ENSP00000327650	P1

Frequencies

GnomAD3 genomes AF: 0.463 AC: 70274 AN: 151908 Hom.: 18761 Cov.: 32

Gnomad AFR AF: 0.635

Gnomad AMI AF: 0.329

Gnomad AMR AF: 0.572

Gnomad ASJ AF: 0.301

Gnomad EAS AF: 0.970

Gnomad SAS AF: 0.570

Gnomad FIN AF: 0.338

Gnomad MID AF: 0.377

Gnomad NFE AF: 0.317

Gnomad OTH AF: 0.459

GnomAD4 exome AF: 0.412 AC: 132546 AN: 322066 Hom.: 32799 Cov.: 0 AF XY: 0.419 AC XY: 72535 AN XY: 173136

Gnomad4 AFR exome AF: 0.644

Gnomad4 AMR exome AF: 0.627

Gnomad4 ASJ exome AF: 0.295

Gnomad4 EAS exome AF: 0.980

Gnomad4 SAS exome AF: 0.547

Gnomad4 FIN exome AF: 0.328

Gnomad4 NFE exome AF: 0.310

Gnomad4 OTH exome AF: 0.399

GnomAD4 genome AF: 0.463 AC: 70386 AN: 152026 Hom.: 18811 Cov.: 32 AF XY: 0.470 AC XY: 34944 AN XY: 74300

Gnomad4 AFR AF: 0.635

Gnomad4 AMR AF: 0.573

Gnomad4 ASJ AF: 0.301

Gnomad4 EAS AF: 0.970

Gnomad4 SAS AF: 0.568

Gnomad4 FIN AF: 0.338

Gnomad4 NFE AF: 0.317

Gnomad4 OTH AF: 0.464

Alfa AF: 0.350 Hom.: 14379

Bravo AF: 0.492

Asia WGS AF: 0.783 AC: 2715 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 31, 2019	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	1.3
DANN	Benign	0.39

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

Other links and lift over

dbSNP: rs12899811; hg19: chr15-91544076;