rs12899811

Variant names:

• chr15-91000846-A-G
• rs12899811
• NM_018668.5:c.1480-255T>C

Your query was ambiguous. Multiple possible variants found:

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

Variant summary

Our verdict is Benign. The variant received -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
• Publications: 65 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: Benign. The variant received -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 VariationId 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 rank	MANE	Protein	UniProt
VPS33B	NM_018668.5	c.1480-255T>C		intron_variant	Intron 19 of 22	ENST00000333371.8	NP_061138.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
VPS33B	ENST00000333371.8	c.1480-255T>C		intron_variant	Intron 19 of 22	1	NM_018668.5	ENSP00000327650.4
ENSG00000284946	ENST00000643536.1	n.1480-255T>C		intron_variant	Intron 19 of 34			ENSP00000494429.1

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

African (AFR) AF: 0.644 AC: 5850 AN: 9086

American (AMR) AF: 0.627 AC: 9460 AN: 15098

Ashkenazi Jewish (ASJ) AF: 0.295 AC: 2748 AN: 9326

East Asian (EAS) AF: 0.980 AC: 18394 AN: 18774

South Asian (SAS) AF: 0.547 AC: 24171 AN: 44202

European-Finnish (FIN) AF: 0.328 AC: 5954 AN: 18128

Middle Eastern (MID) AF: 0.386 AC: 509 AN: 1318

European-Non Finnish (NFE) AF: 0.310 AC: 58440 AN: 188552

Other (OTH) AF: 0.399 AC: 7020 AN: 17582

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

African (AFR) AF: 0.635 AC: 26342 AN: 41458

American (AMR) AF: 0.573 AC: 8760 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.301 AC: 1044 AN: 3470

East Asian (EAS) AF: 0.970 AC: 5024 AN: 5180

South Asian (SAS) AF: 0.568 AC: 2738 AN: 4820

European-Finnish (FIN) AF: 0.338 AC: 3567 AN: 10546

Middle Eastern (MID) AF: 0.381 AC: 112 AN: 294

European-Non Finnish (NFE) AF: 0.317 AC: 21522 AN: 67956

Other (OTH) AF: 0.464 AC: 978 AN: 2106

Alfa AF: 0.364 Hom.: 36368

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

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Jul 31, 2019

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	1.3
DANN	Benign	0.39
PhyloP100		-0.48
Mutation Taster		=100/0	polymorphism (auto)

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: rs12899811; hg19: chr15-91544076;