15-90999318-GTTTT-GTTTTT

Variant names:

• chr15-90999318-G-GT
• rs199831273
• NM_018668.5:c.1775-265dupA

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP6_Moderate BA1

The NM_018668.5(VPS33B):​c.1775-265dupA variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.229 in 429,292 control chromosomes in the GnomAD database, including 1,889 homozygotes. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.12 (1629 hom., cov: 29)
  • Exomes 𝑓: 0.28 (260 hom.)
• Consequence: VPS33B NM_018668.5 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -1.24

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:):

ACMG classification

Verdict is Benign. Variant got -10 ACMG points.

• BP6: Variant 15-90999318-G-GT is Benign according to our data. Variant chr15-90999318-G-GT is described in ClinVar as [Benign]. Clinvar id is 1278236.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.452 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
VPS33B	NM_018668.5	c.1775-265dupA		intron_variant	Intron 22 of 22	ENST00000333371.8	NP_061138.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
VPS33B	ENST00000333371.8	c.1775-265_1775-264insA		intron_variant	Intron 22 of 22	1	NM_018668.5	ENSP00000327650.4
ENSG00000284946	ENST00000643536.1	n.1774+358_1774+359insA		intron_variant	Intron 22 of 34			ENSP00000494429.1

Frequencies

GnomAD3 genomes AF: 0.121 AC: 17717 AN: 146404 Hom.: 1628 Cov.: 29

Gnomad AFR AF: 0.107

Gnomad AMI AF: 0.0580

Gnomad AMR AF: 0.250

Gnomad ASJ AF: 0.0811

Gnomad EAS AF: 0.468

Gnomad SAS AF: 0.197

Gnomad FIN AF: 0.0775

Gnomad MID AF: 0.114

Gnomad NFE AF: 0.0776

Gnomad OTH AF: 0.131

GnomAD4 exome AF: 0.284 AC: 80463 AN: 282852 Hom.: 260 Cov.: 0 AF XY: 0.285 AC XY: 42928 AN XY: 150540

Gnomad4 AFR exome AF: 0.310

Gnomad4 AMR exome AF: 0.381

Gnomad4 ASJ exome AF: 0.248

Gnomad4 EAS exome AF: 0.435

Gnomad4 SAS exome AF: 0.339

Gnomad4 FIN exome AF: 0.251

Gnomad4 NFE exome AF: 0.254

Gnomad4 OTH exome AF: 0.281

GnomAD4 genome AF: 0.121 AC: 17717 AN: 146440 Hom.: 1629 Cov.: 29 AF XY: 0.127 AC XY: 9006 AN XY: 71186

Gnomad4 AFR AF: 0.107

Gnomad4 AMR AF: 0.250

Gnomad4 ASJ AF: 0.0811

Gnomad4 EAS AF: 0.468

Gnomad4 SAS AF: 0.196

Gnomad4 FIN AF: 0.0775

Gnomad4 NFE AF: 0.0776

Gnomad4 OTH AF: 0.133

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Aug 20, 2019

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

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: rs199831273; hg19: chr15-91542548;