rs16945153

Positions:

• chr15-90999901-T-A

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP6_Very_Strong BA1

The NM_018668.5(VPS33B):​c.1656A>T​(p.Thr552Thr) variant causes a splice region, synonymous change. The variant allele was found at a frequency of 0.0102 in 1,614,110 control chromosomes in the GnomAD database, including 1,400 homozygotes. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.053 (713 hom., cov: 32)
  • Exomes 𝑓: 0.0058 (687 hom.)
• Consequence: VPS33B NM_018668.5 splice_region, synonymous
• Scores: Splicing: ADA: 0.9942
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 3.65

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 -16 ACMG points.

• BP6: Variant 15-90999901-T-A is Benign according to our data. Variant chr15-90999901-T-A is described in ClinVar as [Benign]. Clinvar id is 261042.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.18 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
VPS33B	NM_018668.5	c.1656A>T	p.Thr552Thr	splice_region_variant, synonymous_variant	21/23	ENST00000333371.8	NP_061138.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
VPS33B	ENST00000333371.8	c.1656A>T	p.Thr552Thr	splice_region_variant, synonymous_variant	21/23	1	NM_018668.5	ENSP00000327650.4
ENSG00000284946	ENST00000643536.1	n.1656A>T		splice_region_variant, non_coding_transcript_exon_variant	21/35			ENSP00000494429.1

Frequencies

GnomAD3 genomes AF: 0.0528 AC: 8032 AN: 152112 Hom.: 708 Cov.: 32

Gnomad AFR AF: 0.183

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0192

Gnomad ASJ AF: 0.00115

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00621

Gnomad FIN AF: 0.0000942

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.000691

Gnomad OTH AF: 0.0344

GnomAD3 exomes AF: 0.0144 AC: 3609 AN: 251472 Hom.: 312 AF XY: 0.0105 AC XY: 1432 AN XY: 135910

Gnomad AFR exome AF: 0.189

Gnomad AMR exome AF: 0.00928

Gnomad ASJ exome AF: 0.00179

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00382

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000431

Gnomad OTH exome AF: 0.00570

GnomAD4 exome AF: 0.00578 AC: 8444 AN: 1461880 Hom.: 687 Cov.: 32 AF XY: 0.00508 AC XY: 3696 AN XY: 727240

Gnomad4 AFR exome AF: 0.193

Gnomad4 AMR exome AF: 0.0101

Gnomad4 ASJ exome AF: 0.00142

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00373

Gnomad4 FIN exome AF: 0.0000187

Gnomad4 NFE exome AF: 0.000316

Gnomad4 OTH exome AF: 0.0129

GnomAD4 genome AF: 0.0530 AC: 8067 AN: 152230 Hom.: 713 Cov.: 32 AF XY: 0.0523 AC XY: 3894 AN XY: 74448

Gnomad4 AFR AF: 0.184

Gnomad4 AMR AF: 0.0192

Gnomad4 ASJ AF: 0.00115

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00580

Gnomad4 FIN AF: 0.0000942

Gnomad4 NFE AF: 0.000691

Gnomad4 OTH AF: 0.0346

Alfa AF: 0.00849 Hom.: 79

Bravo AF: 0.0611

Asia WGS AF: 0.0150 AC: 53 AN: 3478

EpiCase AF: 0.000545

EpiControl AF: 0.000296

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 31, 2019	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

-

- -

Arthrogryposis, renal dysfunction, and cholestasis 1 Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.32
CADD	Benign	18
DANN	Benign	0.88

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	0.99
dbscSNV1_RF	Pathogenic	0.95
SpliceAI score (max)		0.10		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: rs16945153; hg19: chr15-91543131;