15-90999251-GT-G

Position:

• chr15-90999251-GT-G

Variant summary

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

The NM_018668.5(VPS33B):​c.1775-198del variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.147 in 648,752 control chromosomes in the GnomAD database, including 11,970 homozygotes. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.18 (3503 hom., cov: 29)
  • Exomes 𝑓: 0.14 (8467 hom.)
• Consequence: VPS33B NM_018668.5 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.271

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 -10 ACMG points.

• BP6: Variant 15-90999251-GT-G is Benign according to our data. Variant chr15-90999251-GT-G is described in ClinVar as [Benign]. Clinvar id is 1245281.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.456 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
VPS33B	NM_018668.5	c.1775-198del		intron_variant		ENST00000333371.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
VPS33B	ENST00000333371.8	c.1775-198del		intron_variant		1	NM_018668.5	P1
VPS33B	ENST00000535906.1	c.1694-198del		intron_variant		2
VPS33B	ENST00000574755.5	c.*1470-198del		intron_variant, NMD_transcript_variant		2
VPS33B	ENST00000557470.5	n.148-198del		intron_variant, non_coding_transcript_variant		5

Frequencies

GnomAD3 genomes AF: 0.177 AC: 26809 AN: 151834 Hom.: 3487 Cov.: 29

Gnomad AFR AF: 0.305

Gnomad AMI AF: 0.0570

Gnomad AMR AF: 0.269

Gnomad ASJ AF: 0.0810

Gnomad EAS AF: 0.472

Gnomad SAS AF: 0.201

Gnomad FIN AF: 0.0730

Gnomad MID AF: 0.131

Gnomad NFE AF: 0.0770

Gnomad OTH AF: 0.169

GnomAD4 exome AF: 0.138 AC: 68494 AN: 496802 Hom.: 8467 Cov.: 0 AF XY: 0.136 AC XY: 36273 AN XY: 265830

Gnomad4 AFR exome AF: 0.311

Gnomad4 AMR exome AF: 0.314

Gnomad4 ASJ exome AF: 0.0729

Gnomad4 EAS exome AF: 0.505

Gnomad4 SAS exome AF: 0.182

Gnomad4 FIN exome AF: 0.0759

Gnomad4 NFE exome AF: 0.0763

Gnomad4 OTH exome AF: 0.139

GnomAD4 genome AF: 0.177 AC: 26866 AN: 151950 Hom.: 3503 Cov.: 29 AF XY: 0.181 AC XY: 13422 AN XY: 74252

Gnomad4 AFR AF: 0.305

Gnomad4 AMR AF: 0.269

Gnomad4 ASJ AF: 0.0810

Gnomad4 EAS AF: 0.472

Gnomad4 SAS AF: 0.199

Gnomad4 FIN AF: 0.0730

Gnomad4 NFE AF: 0.0770

Gnomad4 OTH AF: 0.170

Alfa AF: 0.129 Hom.: 256

Bravo AF: 0.201

Asia WGS AF: 0.314 AC: 1090 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Nov 12, 2018

- -

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: rs75453156; hg19: chr15-91542481;